Concept of Elemental Impurities (EI) assessment in finished dosage forms by

total extraction testing

W. Keurentjes, F. Maris, T. Wang, M. van Tiel

Merck & Co.

Content

• Introduction

• How did we start…

• Straight forward procedure

• Feasibility study

• ‘total’ extraction

• Results

• Validation aspects

• Conclusions

Introduction

• Wilfried Keurentjes

– ICP-MS laboratory Merck & Co. - The Netherlands

– Merck & Co. platform for implementing EI

Two approaches:

• Option 1: API/Excipient gathering info

• Option 2: Finished dosage form testing

How did we start…

Option 1: collection EI information of all APIs/Excipients

• Incoming materials approach – Over 50 sites with more than 100 drug products

– Over 5000 excipients and API’s

– Many different suppliers/production locations for excipients

• It was impossible to get the information on EI from the excipients suppliers (since they are on the same compliance schedule as we are) and the quality of the information we did receive was questionable.

• Will this approach give full information on a finished dosage form?

Straight forward procedure

Option 2: Approach finished dosage form (DP) testing

• Analyze 3 commercial batches of each DP “worst case” strength – Option: use stability batches as worst case e.g. include migration of EI

from the primary packaging (according guideline not mandatory)

– Different batches excipients, API e.g. use 1, 2 and 3 year old stability samples (for products with shelf life >= 36 months)

• Use one standardized, straight forward analytical procedure

• Execute as limit test on 30% requirement

• Execute sample related validity tests during analysis

Straight forward procedure

• To cover the wide range of Merck products and PDEs (based on routes of administration and daily dose) we selected ICP-MS as the technique of preference.

• Experience with ICP-MS analysis is available at several labs at Merck.

• Experience on sample prep of drug products is limited. Therefore a feasibility study was started

Feasibility study

• One sample prep (and ICP-MS) method for all our products addressing all class 1 to 3 elements! Method must be efficient and cost effective

• Sample prep options:

– Total analysis • For many products microwave digestion is needed which is very

laborious

– Gastrointestinal extraction • No clear guidelines and only suitable for oral products

– Simplified nearly ‘total’ extraction • 80% of concentrated nitric acid at room temperature over 16+

hours.

Feasibility study

Standardized method:

• Put product in a tube (duplicate + standard addition)

• Add 5 mL water – disintegrate / dissolve

• Add 20 mL conc. Nitric acid for a final concentration of 80% nitric acid – dissolve / extract / digest

• Shake the samples for over 16 hours (overnight) and settle.

• Dilute if necessary

• Analyze all products in one ICP-MS run

‘total’-extraction

Pro

• Strong acid will dissolve most salt or metals

• Digest or dissolve many organic compounds.

• Efficient

Con

• Safety precautions (nitrous oxide fumes)

• Not always a total extraction but the method is fit for purpose

‘total’-extraction

Main question.

• Is total analysis required? E.g. elements locked into a lattice might not be relevant because they will not be absorbed. (Q3D tox studies mainly used readily available salts)

• Statement: The 80% of concentrated nitric acid medium will be used to distinguish relevant and not relevant parts, since it is a very vigorous medium. The method is fit for purpose

Results of the Feasibility Study

The study has been performed on 16 chosen (parenteral/oral/special) products

Results of the Feasibility Study

• All selected products comply with 30% PDE rule using the 10 g/day option. – simplify lab calculations

– not applicable for all products e.g. inhalator, implants?

• Efficient: During this first study of 4 days, 16 products were analyzed in duplicate and a spike addition.

• Analytical, some minor issues

Results of the Feasibility Study

Not all products did dissolve.

• Polymeric Dissolving is not needed.

• Oil products Shaking during 16 hours of extraction to assure good contact between product and acid medium for all products will be added to the method

Results of the Feasibility Study

• Lithium sensitivity is lower than other elements. But 30% of limits can be achieved

• Re-analysis of QC-standard 10 ng/mL during run gave some deviations > 20% for Li and Os

• Some recoveries deviate from 80-120% (As, Ag, Os, Pd, and Li) – addition of 0.5% hydrochloric acid to the acid medium would mitigate

• Blank level of Pb is raised 1 ng/mL. Controlling contamination is a day to day responsibility of the lab.

Validation aspects Validation aspect During analysis

(on samples) Validation report (on solutions)

Accuracy Spike recovery 70 – 150%

Drift QC sample NMT 20%

Precision - repeatability Two solutions in six fold - NMT 20% 1. High salt matrix 2. High carbon matrix

Precision - ruggedness As repeatability, over three days - NMT 25%

Specificity (Elemental) interferences 1. High salt matrix 2. High carbon matrix

Limit of Quantitation 30% of 0,5 of lowest J must comply

Linearity / Range r > 0,99 (no need for ½J / 2J)

At least from 30% of 0,5 of lowest J to 2 times highest J r > 0,99

Conclusion

Assessment of elemental impurities in finished dosage forms by total extraction testing

- Method proved to work on 16 products

- Efficient

- Holistic results including factors as API, excipients, environment, prim. packaging and stability.

Questions, Remarks