Q3D - Elemental Impurities:What implications for
APIs & excipients suppliers?
European leader in analytical sciences
Written by:Philippe De Raeve, Scientific Director, R&D
V3 15/10/2015
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20140121
ICH Q3D
Q3D Step 4 was published on 16th December 2014
Different organisations are involved in the implementation
of this guideline: FDA, USP, EMA, EDQM…
What are the application DATES ?
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20140121
EMA&EDQM Position
EMA
Q3D applicable for new marketing authorization: June 2016
Q3D applicable for existing marketed products: December 2017
EDQM
Will replace content of chapter 5.20 (currently: “Metal Catalysts or Metal Reagent
Residues”) by Q3D (verbatim reproduction in suppl 9.3 of Ph. Eur.)
Reference to 5.20 will be made in 2619 (Pharmaceutical preparations), making
Q3D mandatory for all medicinal products
Implementation date: 1/1/2018
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20140121
USP&FDA Position
USP
Revised <232> & <233> were published in 2nd supplement of USP38 (June 1, 2015) and
will become official on December 1, 2015
<231> will remain in effect until 01/01/2018 but USP allows and encourages users to
implement the new methods ASAP.
<232> mandatory on January 1, 2018 for USP Drug Products
FDA:
Notice of Q3D availability was published in the Federal Register in September 2015
Implementation dates are the same as EMA :
- June 2016 for new DP
- 1/1/2018 for existing DP
JAPAN:
Implementation date for new drug products: 1st April 2017
(Not yet clear for existing drug products)
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20140121
Q3D: notonlyforDrugProducts ?
Q3D specifications are for Drug Products only, but…..
Drug product manufacturers must carry out a risk assessment to identify
and control elemental impurities, considering all potential sources.
Q3D, § 5 excerpt: “Information for this risk assessment includes but is
not limited to: data generated by the applicant, information supplied
by drug substance and/or excipient manufacturers and/or data
available in published literature.”
USP: notonlyforDrugProducts ?
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20140121
USP <232> excerpt:
“The limits presented in this chapter do not apply to excipients and DS.
However, elemental impurity levels present in drug substances and
excipients must be known, documented, and made available upon
request” !
Consequence forAPIs&Excipients suppliers
As a consequence, Drug Product manufacturers will
require from suppliers of APIs and excipients to
provide specifications and/or batch analysis for all
their products !
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Element ClassOral PDE(µg/day)
Parenteral PDE(µg/day)
Inhalation PDE(µg/day)
Cd 1 5 2 2
Pb 1 5 5 5
As 1 15 15 2
Hg 1 30 3 1
Co 2A 50 5 3
V 2A 100 10 1
Ni 2A 200 20 5
Tl 2B 8 8 8
Au 2B 100 100 1
Pd 2B 100 10 1
Ir 2B 100 10 1
Os 2B 100 10 1
Rh 2B 100 10 1
Ru 2B 100 10 1
Se 2B 150 80 130
Ag 2B 150 10 1
Pt 2B 100 10 1
Li 3 550 250 25
Sb 3 1200 90 20
Ba 3 1400 700 300
Mo 3 3000 1500 10
Cu 3 3000 300 30
Sn 3 6000 600 60
Cr 3 11000 1100 3
20140121
Q3DElemental impurities: PDEs
Implementation for new products: June 2016
Implementation for existing products: 1st January 2018
Thousands of Pharma Products will have to comply
Many drug substances and excipients will also have to be analyzed
Impossible to develop and validate one method for each DP, API and excipient !
NEED FOR A GENERIC METHOD
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CURRENT SITUATION SUMMARY
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Quality Assistance solution
Quality Assistance has developed and validated a generic method applicable to
many kinds of sample, either drug product, or API, or excipient.
It allows determination of the 23 elements of Q3D (except Osmium) in a single run.
Aluminium was added to this list to cope with other regulations.
ICP-MS provides high sensitivity, allowing to extend the range of the method well
below the specified limits
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QA GENERIC METHOD CHARACTERISTICS (1)
For 23 Elemental Impurities of ICH Q3D + Al
(except Os: need for a separate method, currently under development )
Systematic microwave digestion with the same mixture of acids :
High temperature and pressure to ensure complete digestion
Same final sample solution solvent
Reduced validation
Control of residual carbon (RCC) :
Check of digestion efficiency
Verification that “carbon effect” is avoided
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QA GENERIC METHOD CHARACTERISTICS (2)
Sample preparation :
Digestion of 200 mg sample
Addition of internal standards
Dilution to 40 mL with a suitable solvent (diluted acids)
Determination by ICP-MS :
Calibration with diluted stock solutions (custom made for QA)
Dilutions done with same solvent as sample (matrix match)
All EI in a single run
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QA GENERIC METHOD CHARACTERISTICS (3)
Range of the method
Method was designed to cover a wide range of elemental impurities concentrations,
adapted to the individual PDEs for each element.
The table in the next slide shows the validated range of the method for a sample to be
tested (API, excipient or DP)
For each element, method includes the narrow range recommended by USP <233>:
(50 – 150 % of the target limit) but was expanded down to much lower concentrations.
For EI with high PDEs, the range was intentionally limited to 20 ug/g to avoid
contamination of the ICP-MS
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Element ClassMethod range
(µg/g)
Max Conc.for 10g/day
oral(µg/g)
Max Conc.for 10g/dayparenteral
(µg/g)
Max Conc.for 1g/dayinhalation
(µg/g)
Cd 1 0.005 - 1.0 0.5 0.2 2Pb 1 0.005 - 1.0 0.5 0.5 5As 1 0.015 – 3.0 1.5 1.5 2Hg 1 0.03 – 6.0 3 0.3 1
Co 2A 0.05 – 10 5 0.5 3V 2A 0.1 – 20 10 1 1Ni 2A 0.2 – 40 20 2 5
Tl 2B 0.008 – 1.6 0.8 0.8 8Au 2B 0.1 – 20 10 10 1Pd 2B 0.1 – 20 10 1 1Ir 2B 0.1 – 20 10 1 1Os 2B NA 10 1 1Rh 2B 0.1 – 20 10 1 1Ru 2B 0.1 – 20 10 1 1Se 2B 0.75 – 30 15 8 130Ag 2B 0.15 – 30 15 1 7Pt 2B 0.1 – 20 10 1 1
Li 3 0.5 – 20 55 25 25Sb 3 0.1 – 20 120 9 20Ba 3 0.1 – 20 140 70 300Mo 3 0.1 – 20 300 150 10Cu 3 1 – 20 300 30 30Sn 3 0.1 – 20 600 60 60Cr 3 0.5 – 20 1100 110 3
Al NA 0.5 – 20 NA NA NA
Validated range of the method
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METHOD VALIDATION
Full validation for BSA, Cellulose & Carbamazepine
Acceptance criteria based on USP <233>, Ph. Eur. 2.4.20 and QA internal procedure
Verification of performance for several other matrixes :
Difficult to digest: PEG, Tannic acid, Phenylalanine
Organic acids: Tannic and Citric acids
Organic bases: Caffeine, TEA
Inorganic salts: NaCl, Na2CO3, KH2PO4
Compound able to complex metals: Cysteine
Metal containing excipient: magnesium stearate
Finished drug product: paracetamol tablets
Validation results
Specificity
Versus digestion mixture and dilution solvent:
Signal for all elements is < LLOQ
Versus sample matrix (BSA, Cellulose & carbamazepine):
Recoveries for spiked sample meet USP precision and accuracy acceptance
criteria
Versus major elements:
Elements not in Q3D but likely to be present in high concentration in some
samples: Al, Ca, Fe, K, Mg, Na, Zn, S and P
Recoveries of the Q3D elements in presence of 2500 µg/mL of major elements
still meet acceptance criteria.
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Validation results
Linearity
Linearity for calibration solutions checked for the complete method range
Correlation coefficient > 0.999 for all elements
Accuracy & Precision
Assessed for BSA, cellulose & carbamazepine
Samples spiked before digestion at 1, 5, 10, 30, 100 and 200 %
3 sample preparations at each level (6 at 100 %)
All recoveries are between 70 – 150 %
RSD < 30 % at LLOQ
RSD < 20 % for all other levels
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Validation results
Intermediate Precision
Same instrument on day 2
New independent calibration
6 new preparations of spiked and unspiked samples
RSD < 20 % for day 2 (n = 6)
RSD < 25 % for cumulated results (n = 12)
Stability
Evaluated for standard and sample solutions
All solutions stable for at least 24 h
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Accuracy, precision and intermediate precisionforBSA
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Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSDCd 102 0.4 102 0.6 102 0.5Pb 99 0.5 98 0.5 99 0.9As 99 0.3 98 0.7 99 0.5Hg 101 0.5 99 0.8 100 1.2
Co 100 0.5 102 0.6 101 1.5V 100 1.0 99 0.6 100 0.9Ni 100 0.4 103 0.7 101 1.7
Tl 100 0.4 99 1.2 99 0.9Au 98 0.6 97 0.4 98 0.6Pd 99 0.3 100 0.3 100 0.6Ir 99 0.5 99 0.6 99 0.6Os - - - - - -Rh 100 0.6 101 0.4 100 0.8Ru 99 0.4 100 0.5 99 0.6Se 101 0.5 100 1.4 101 1.1Ag 96 0.8 97 0.3 96 0.9Pt 99 0.6 99 0.5 99 0.6
Li 92 2.0 100 2.3 96 4.9Sb 100 0.8 95 0.5 97 2.5Ba 100 0.7 96 0.7 98 2.0Mo 102 0.5 102 0.6 102 0.6Cu 100 0.7 101 1.2 100 1.3Sn 99 0.5 95 0.8 97 2.5Cr 98 1.0 99 1.7 98 1.5
Al 97 1.9 100 3.8 99 3.1
Min recovery: 92 %
Max recovery: 102 %
Max RSD: 4.9 %
Accuracy, precision and intermediate precisionforCellulose
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Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSDCd 101 0.6 103 0.4 102 1.1Pb 100 1.3 101 0.3 100 1.0As 100 0.3 100 0.7 100 0.6Hg 99 0.4 99 1.0 99 0.7
Co 106 0.5 106 0.5 106 0.5V 98 1.3 99 0.9 99 1.2Ni 106 0.8 106 0.9 106 0.8
Tl 100 0.8 101 0.9 101 1.1Au 99 0.4 99 0.6 99 0.6Pd 102 0.5 103 0.2 103 0.5Ir 101 0.6 101 0.7 101 0.7Os - - - - - -Rh 104 0.9 104 0.4 104 0.7Ru 103 0.8 103 0.4 103 0.7Se 101 0.8 101 0.9 101 0.9Ag 101 0.4 102 0.6 101 0.5Pt 100 0.6 101 0.3 100 0.5
Li 105 2.2 103 1.6 104 2.0Sb 96 0.5 96 0.6 96 0.6Ba 96 0.5 97 0.7 97 0.7Mo 102 0.6 102 0.4 102 0.5Cu 104 0.7 106 0.5 105 0.9Sn 96 0.3 95 0.7 96 0.7Cr 98 1.1 100 1.0 99 1.2
Al 99 2.0 103 3.3 101 3.3
Min recovery: 95 %
Max recovery: 106 %
Max RSD: 3.3 %
Accuracy, precision and intermediate precision for Carbamazepine
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Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSDCd 103 2.3 104 0.7 104 1.7Pb 101 1.6 101 0.6 101 1.2As 104 1.8 101 0.5 102 2.2Hg 101 2.1 99 1.3 100 2.0
Co 107 2.3 108 1.1 108 1.8V 100 2.0 98 1.0 99 1.9Ni 108 2.3 109 0.7 108 1.8
Tl 101 1.6 102 1.2 102 1.5Au 102 1.6 99 0.5 101 2.1Pd 105 2.0 104 0.6 104 1.5Ir 104 2.5 100 1.9 102 2.7Os - - - - - -Rh 105 1.8 105 0.6 105 1.3Ru 104 1.8 104 0.5 104 1.3Se 101 1.8 100 0.5 100 1.4Ag 102 1.7 98 1.1 100 2.4Pt 102 1.9 100 0.8 101 1.8
Li 107 2.3 105 0.9 106 2.0Sb 98 1.9 95 1.0 96 2.5Ba 98 2.1 96 1.1 97 2.0Mo 105 1.8 103 0.9 104 1.5Cu 108 2.3 108 0.9 108 1.6Sn 99 1.8 93 0.7 96 3.5Cr 101 2.2 100 5.6 101 4.1
Al 103 3.2 101 2.5 102 2.9
Min recovery: 93 %
Max recovery: 108%
Max RSD: 4.1 %
Method performance verification
Verification procedure
12 widely different sample matrices
For each sample, 3 unspiked & 3 spiked (before digestion) preparations
Recoveries and RSDs calculated for each element after subtraction of
average natural content
See results in following tables
RCC also measured for all samples (spiked or unspiked)
RCC << 0.1 mg/mL
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Performance verification
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Element PEG Phenylalanine Tannic acid Caffeine Cysteine Citric acid
Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSDCd 102 0.6 102 0.6 103 0.6 103 0.9 98 0.8 98 0.6Pb 102 0.2 101 0.1 102 0.2 101 0.9 100 0.0 99 0.5As 101 0.6 100 0.7 100 0.3 99 0.3 104 0.7 100 0.5Hg 101 0.5 99 0.8 99 0.9 97 0.8 99 0.9 99 0.4
Co 105 0.9 106 0.3 108 0.8 107 0.7 97 1.3 98 0.4V 98 0.9 98 0.6 98 0.3 97 0.1 102 0.3 100 0.5Ni 106 0.7 107 0.3 108 0.6 108 1.2 98 1.1 99 0.4
Tl 101 1.1 101 0.7 101 0.7 101 1.7 99 0.7 99 0.5Au 98 0.4 97 0.1 97 0.8 96 0.6 98 0.3 99 0.1Pd 102 0.7 102 0.1 103 0.2 103 0.6 100 0.8 100 0.2Ir 100 0.2 99 0.3 99 0.4 99 0.5 101 0.3 101 0.2Os - - - - - - - - - - - -Rh 104 0.4 105 0.3 106 0.5 106 0.3 101 0.6 102 0.1Ru 103 0.7 103 0.4 104 0.5 103 0.4 98 1.0 99 0.2Se 102 0.3 101 0.8 102 0.9 102 0.6 122 0.4 102 1.0Ag 96 0.7 95 0.9 100 0.4 101 0.9 99 0.3 100 0.3Pt 100 0.6 100 0.5 100 0.3 101 0.1 101 0.0 101 0.2
Li 99 2.8 100 1.4 99 1.7 97 1.7 99 2.4 105 0.8Sb 97 0.5 97 0.4 97 0.6 95 0.4 101 0.7 100 1.5Ba 97 0.8 96 0.3 96 1.2 96 1.1 103 1.0 102 0.8Mo 103 0.6 103 0.6 104 0.8 104 0.7 96 1.9 97 0.4Cu 105 0.3 105 0.4 107 0.7 106 0.8 100 1.0 100 0.5Sn 97 0.7 97 0.5 96 0.7 94 0.3 101 0.9 102 1.0Cr 97 1.4 97 0.6 97 0.1 96 0.5 102 0.2 101 0.4
Al 100 1.6 96 2.3 98 5.5 99 3.7 102 3.0 101 2.2
Performance verification
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Element Na2CO3 NaCl KH2PO4 TEAParacetamol
TabsMg Stearate
Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSDCd 109 0.8 105 0.7 113 0.6 109 0.25 107 0.8 114 0.7Pb 100 0.5 98 0.2 100 0.3 103 0.6 100 0.8 100 0.5As 106 0.4 105 0.9 107 0.4 100 0.6 99 0.9 102 0.4Hg 102 0.0 101 0.5 98 09 97 0.2 96 0.7 95 0.2
Co 111 0.4 103 1.7 117 0.6 113 0.5 109 0.2 122 0.8V 100 0.4 100 0.4 98 1.2 96 1.1 97 1.2 100 0.7Ni 106 0.6 98 2.7 112 0.4 111 0.9 107 0.4 117 0.8
Tl 100 0.6 98 0.7 101 0.7 102 1.6 98 0.9 100 1.0Au 95 0.6 96 0.4 91 0.4 95 0.8 94 0.6 90 0.9Pd 97 0.1 94 1.3 99 0.4 103 0.7 101 0.3 102 0.2Ir 97 0.2 98 0.5 95 0.3 97 0.4 96 0.5 95 0.4Os - - - - - - - - - - - -Rh 101 0.2 95 1.3 103 0.4 104 0.4 103 0.3 107 0.1Ru 102 0.8 97 1.2 103 0.6 105 0.5 103 0.9 109 0.3Se 113 0.6 110 0.8 117 0.5 110 0.7 108 0.8 112 0.9Ag 94 0.1 92 0.8 94 0.4 101 1.4 97 1.5 102 0.3Pt 95 0.5 96 0.3 92 0.7 95 0.9 95 0.4 90 0.4
Li 90 1.6 92 1.2 98 1.3 101 0.9 99 1.4 102 0.9Sb 97 1.0 100 1.3 94 0.0 95 0.7 93 3.6 89 0.4Ba 94 0.4 96 0.6 90 0.5 95 1.1 95 0.9 87 0.6Mo 111 0.2 104 1.3 115 0.6 106 0.3 105 0.9 117 0.8Cu 103 1.0 131 6.8 108 0.0 109 0.2 106 0.2 113 0.5Sn 91 0.3 94 1.4 91 0.4 94 0.6 94 0.8 86 0.8Cr 92 0.5 94 3.0 89 1.1 94 1.0 94 1.4 93 1.0
Al 106 2.3 104 3.9 105 1.3 106 0.6 104 2.9 107 3.3
CONCLUSION
The generic method was fully validated for 3 matrices: BSA, Cellulose & Carbamazepine
Its performance was also verified for 12 widely different matrices.
Systematic digestion brings all samples in the same final solvent, allowing reduced
validation work
Simple verification of performance rather than a complete validation
This method was extensively validated to guarantee reliable results and offers a
sufficient degree of confidence for finalization of risk assessment.
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QUALITY ASSISTANCE PROPOSAL
For APIs and excipients
Using our generic method, analyze 3 batches of API or of excipient, taken at the end of shelf
life; in such way, all potential sources of EI will be taken into account, even coming from the
manufacturing process or leaching from CCS.
Mined excipients may require analysis of more than 3 batches in order to take into account
the high variability inherent to this type of natural product.
In some cases, analysis of all batches may be necessary.
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QUALITY ASSISTANCE PROPOSAL
For existing drug products
Using our generic method, analyze 3 batches of drug product, taken at the end of shelf life,
in such way, all potential sources of EI will be taken into account, even coming from the
manufacturing process or leaching from CCS.
- if all EI < 30 % of PDE: NO ADDITIONAL CONTROL !
- if one or more EI is between 30 % and 100 % of PDE
Identify the source
Reduce EI content
or
establish specifications and controls (for DP or component)
(a specific validated method will be required)
If an EI is > 100 % PDE: reduce EI level (or justify levels > PDE)
Change quality or supplier of the component source of the problem
Change manufacturing equipment responsible of the contamination
Change container closure system
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QUALITY ASSISTANCE PROPOSAL
For new drug product
Select components and container closure system on basis of supplier information
If information is not available, carry out a screening of EI for components and/or CCS
(Quality Assistance generic method is also suitable for this purpose)
Early assessment of EI in formulation components may avoid non-compliant DP
EI from manufacturing process ?
Using our generic method, analyze 3 batches of drug product
EI potentially leached from CCS should be adressed during stability studies
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OSMIUM