q3d - elemental impurities: what implications for apis & excipients suppliers?

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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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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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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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


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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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


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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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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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

q3d - elemental impurities: what implications for apis & excipients suppliers?

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