ICH Q3D Step4 will have to be applied very soon: June 2016 for new Drug Products and 1st January 2018 for all existing DP, making it mandatory for all manufacturers to carry out a risk assessment to control elemental impurities in their DP. Such evaluation needs to consider all potential sources of Elemental Impurities and obviously, drug product components are probably the most likely contributors. by Dr Ph. De Raeve, Scientific Director For more informations : www.quality-assistance.com

1. 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

2. 2
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 ?

3. 3
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

4. 4
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)

5. 5
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.”

6. USP: notonlyforDrugProducts?
6
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” !

7. ConsequenceforAPIs&Excipientssuppliers
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 !
7

8. 8
Element Class
Oral 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

9. 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
9
CURRENT SITUATION SUMMARY

10. 10
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

11. 11
QA GENERIC METHODCHARACTERISTICS(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

12. 12
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

13. 13
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

14. 14
Element Class
Method range
(µg/g)
Max Conc.
for 10g/day
oral
(µg/g)
Max Conc.
for 10g/day
parenteral
(µg/g)
Max Conc.
for 1g/day
inhalation
(µg/g)
Cd 1 0.005 - 1.0 0.5 0.2 2
Pb 1 0.005 - 1.0 0.5 0.5 5
As 1 0.015 – 3.0 1.5 1.5 2
Hg 1 0.03 – 6.0 3 0.3 1
Co 2A 0.05 – 10 5 0.5 3
V 2A 0.1 – 20 10 1 1
Ni 2A 0.2 – 40 20 2 5
Tl 2B 0.008 – 1.6 0.8 0.8 8
Au 2B 0.1 – 20 10 10 1
Pd 2B 0.1 – 20 10 1 1
Ir 2B 0.1 – 20 10 1 1
Os 2B NA 10 1 1
Rh 2B 0.1 – 20 10 1 1
Ru 2B 0.1 – 20 10 1 1
Se 2B 0.75 – 30 15 8 130
Ag 2B 0.15 – 30 15 1 7
Pt 2B 0.1 – 20 10 1 1
Li 3 0.5 – 20 55 25 25
Sb 3 0.1 – 20 120 9 20
Ba 3 0.1 – 20 140 70 300
Mo 3 0.1 – 20 300 150 10
Cu 3 1 – 20 300 30 30
Sn 3 0.1 – 20 600 60 60
Cr 3 0.5 – 20 1100 110 3
Al NA 0.5 – 20 NA NA NA
Validated range of the method

15. 15
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

16. Validationresults
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.
16

17. 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
17

18. 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
18

19. Accuracy, precision and intermediate precisionforBSA
19
Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSD
Cd 102 0.4 102 0.6 102 0.5
Pb 99 0.5 98 0.5 99 0.9
As 99 0.3 98 0.7 99 0.5
Hg 101 0.5 99 0.8 100 1.2
Co 100 0.5 102 0.6 101 1.5
V 100 1.0 99 0.6 100 0.9
Ni 100 0.4 103 0.7 101 1.7
Tl 100 0.4 99 1.2 99 0.9
Au 98 0.6 97 0.4 98 0.6
Pd 99 0.3 100 0.3 100 0.6
Ir 99 0.5 99 0.6 99 0.6
Os - - - - - -
Rh 100 0.6 101 0.4 100 0.8
Ru 99 0.4 100 0.5 99 0.6
Se 101 0.5 100 1.4 101 1.1
Ag 96 0.8 97 0.3 96 0.9
Pt 99 0.6 99 0.5 99 0.6
Li 92 2.0 100 2.3 96 4.9
Sb 100 0.8 95 0.5 97 2.5
Ba 100 0.7 96 0.7 98 2.0
Mo 102 0.5 102 0.6 102 0.6
Cu 100 0.7 101 1.2 100 1.3
Sn 99 0.5 95 0.8 97 2.5
Cr 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 %

20. Accuracy, precision and intermediate precisionforCellulose
20
Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSD
Cd 101 0.6 103 0.4 102 1.1
Pb 100 1.3 101 0.3 100 1.0
As 100 0.3 100 0.7 100 0.6
Hg 99 0.4 99 1.0 99 0.7
Co 106 0.5 106 0.5 106 0.5
V 98 1.3 99 0.9 99 1.2
Ni 106 0.8 106 0.9 106 0.8
Tl 100 0.8 101 0.9 101 1.1
Au 99 0.4 99 0.6 99 0.6
Pd 102 0.5 103 0.2 103 0.5
Ir 101 0.6 101 0.7 101 0.7
Os - - - - - -
Rh 104 0.9 104 0.4 104 0.7
Ru 103 0.8 103 0.4 103 0.7
Se 101 0.8 101 0.9 101 0.9
Ag 101 0.4 102 0.6 101 0.5
Pt 100 0.6 101 0.3 100 0.5
Li 105 2.2 103 1.6 104 2.0
Sb 96 0.5 96 0.6 96 0.6
Ba 96 0.5 97 0.7 97 0.7
Mo 102 0.6 102 0.4 102 0.5
Cu 104 0.7 106 0.5 105 0.9
Sn 96 0.3 95 0.7 96 0.7
Cr 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 %

21. Accuracy, precision and intermediate precision for Carbamazepine
21
Element Day 1 (n=6) Day 2 (n=6) Combined (n=12)
% Recovery % RSD % Recovery % RSD % Recovery % RSD
Cd 103 2.3 104 0.7 104 1.7
Pb 101 1.6 101 0.6 101 1.2
As 104 1.8 101 0.5 102 2.2
Hg 101 2.1 99 1.3 100 2.0
Co 107 2.3 108 1.1 108 1.8
V 100 2.0 98 1.0 99 1.9
Ni 108 2.3 109 0.7 108 1.8
Tl 101 1.6 102 1.2 102 1.5
Au 102 1.6 99 0.5 101 2.1
Pd 105 2.0 104 0.6 104 1.5
Ir 104 2.5 100 1.9 102 2.7
Os - - - - - -
Rh 105 1.8 105 0.6 105 1.3
Ru 104 1.8 104 0.5 104 1.3
Se 101 1.8 100 0.5 100 1.4
Ag 102 1.7 98 1.1 100 2.4
Pt 102 1.9 100 0.8 101 1.8
Li 107 2.3 105 0.9 106 2.0
Sb 98 1.9 95 1.0 96 2.5
Ba 98 2.1 96 1.1 97 2.0
Mo 105 1.8 103 0.9 104 1.5
Cu 108 2.3 108 0.9 108 1.6
Sn 99 1.8 93 0.7 96 3.5
Cr 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 %

22. 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
22

23. Performance verification
23
Element PEG Phenylalanine Tannic acid Caffeine Cysteine Citric acid
Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD
Cd 102 0.6 102 0.6 103 0.6 103 0.9 98 0.8 98 0.6
Pb 102 0.2 101 0.1 102 0.2 101 0.9 100 0.0 99 0.5
As 101 0.6 100 0.7 100 0.3 99 0.3 104 0.7 100 0.5
Hg 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 0.4
V 98 0.9 98 0.6 98 0.3 97 0.1 102 0.3 100 0.5
Ni 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 0.5
Au 98 0.4 97 0.1 97 0.8 96 0.6 98 0.3 99 0.1
Pd 102 0.7 102 0.1 103 0.2 103 0.6 100 0.8 100 0.2
Ir 100 0.2 99 0.3 99 0.4 99 0.5 101 0.3 101 0.2
Os - - - - - - - - - - - -
Rh 104 0.4 105 0.3 106 0.5 106 0.3 101 0.6 102 0.1
Ru 103 0.7 103 0.4 104 0.5 103 0.4 98 1.0 99 0.2
Se 102 0.3 101 0.8 102 0.9 102 0.6 122 0.4 102 1.0
Ag 96 0.7 95 0.9 100 0.4 101 0.9 99 0.3 100 0.3
Pt 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 0.8
Sb 97 0.5 97 0.4 97 0.6 95 0.4 101 0.7 100 1.5
Ba 97 0.8 96 0.3 96 1.2 96 1.1 103 1.0 102 0.8
Mo 103 0.6 103 0.6 104 0.8 104 0.7 96 1.9 97 0.4
Cu 105 0.3 105 0.4 107 0.7 106 0.8 100 1.0 100 0.5
Sn 97 0.7 97 0.5 96 0.7 94 0.3 101 0.9 102 1.0
Cr 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

24. Performance verification
24
Element Na2CO3 NaCl KH2PO4 TEA
Paracetamol
Tabs
Mg Stearate
Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD Recovery RSD
Cd 109 0.8 105 0.7 113 0.6 109 0.25 107 0.8 114 0.7
Pb 100 0.5 98 0.2 100 0.3 103 0.6 100 0.8 100 0.5
As 106 0.4 105 0.9 107 0.4 100 0.6 99 0.9 102 0.4
Hg 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 0.8
V 100 0.4 100 0.4 98 1.2 96 1.1 97 1.2 100 0.7
Ni 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 1.0
Au 95 0.6 96 0.4 91 0.4 95 0.8 94 0.6 90 0.9
Pd 97 0.1 94 1.3 99 0.4 103 0.7 101 0.3 102 0.2
Ir 97 0.2 98 0.5 95 0.3 97 0.4 96 0.5 95 0.4
Os - - - - - - - - - - - -
Rh 101 0.2 95 1.3 103 0.4 104 0.4 103 0.3 107 0.1
Ru 102 0.8 97 1.2 103 0.6 105 0.5 103 0.9 109 0.3
Se 113 0.6 110 0.8 117 0.5 110 0.7 108 0.8 112 0.9
Ag 94 0.1 92 0.8 94 0.4 101 1.4 97 1.5 102 0.3
Pt 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 0.9
Sb 97 1.0 100 1.3 94 0.0 95 0.7 93 3.6 89 0.4
Ba 94 0.4 96 0.6 90 0.5 95 1.1 95 0.9 87 0.6
Mo 111 0.2 104 1.3 115 0.6 106 0.3 105 0.9 117 0.8
Cu 103 1.0 131 6.8 108 0.0 109 0.2 106 0.2 113 0.5
Sn 91 0.3 94 1.4 91 0.4 94 0.6 94 0.8 86 0.8
Cr 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

25. 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.
25

26. 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.
26

27. 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
27

28. 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
28

29. OSMIUM