trace element analysis in pharmaceutical products

||Trace Element Analysis in Pharmaceutical ProductsAnalytical Strategy

Analytical Strategy HS2019

Trace Element Analysis in Pharmaceutical Products

10/01/2019 1Gaël Mourouga, Corina Meyer


You are an analytical scientist in the trace element team of a contractlaboratory which works largely according to quality standard GMP (goodmanufacturing practice).

Imagine you have nearly unlimited equipment available.

10/01/2019Gaël Mourouga, Corina Meyer 2

Introduction


A customer from a large pharmaceutical company comes to you becausethey have a problem with one of their production sites where theyproduce a precious API (active pharmaceutical ingredient):

They have found a hair crack in one of their centrifuges and black,greasy material outside of the container. They contact you for help.


Troubleshooting


Why is your customer concerned? What are the potentialrisks? Contamination of the API If unnoticed contamination: Toxic effects in patients Reputational damage Financial loss Loss of API Health risk for employees


Troubleshooting: Potential Risks


What might the dark matter coming out of the centrifuge becomposed of?


Troubleshooting: Origin of the Problem

||Trace Element Analysis in Pharmaceutical ProductsAnalytical Strategy 10/01/2019Gaël Mourouga, Corina Meyer 6


Black color

Normal:

Presence of molybdenum disulphide

Abnormal:

Oxidation due to presence of metallic particles



Leak?

Source: researchgate.net, K.saengchan et al. DOI: 10.1016/j.seppur.2014.02.026



Sealing problem Mechanical problem Lubrication problem

• Leakage from the tanks to the bearings

• Presence of solvent leading to corrosion

• Small deviation of the axis from the vertical position

• Leads to parasitic vibrations, repeated shocks and material fatigue

• Lack of lubrication on the bearings

• Leads to abrasion


Troubleshooting: Mechanical AnalysisVibration analysis

Source: https://vibralign.com/resources/concepts/vibration-analysis/

Accelerometer Computer Vibration modesVibrations → electric signal Fast Fourier transform Information on rotor

components


Troubleshooting: Analysis of the «black, greasymaterial»

Bulk analysis: Particle Quantifying Index



Magnetic field Ferromagnetic content of the oilperturbation

PQI

Sample



OK or slightly increased Increased Extreme

Source: https://www.machinerylubrication.com/Read/296/grease-analysis

High



After filtration: Atomic Emission Spectroscopy, Rotrode method

Source: https://en.oelcheck.com/analyses/test-methods/elements-aes-rotrode/

Spectroil Q100



Atomic Emission Spectroscopy, Rotrode method

Source: https://en.oelcheck.com/analyses/test-methods/elements-aes-rotrode/

Electric Arc photocellsCrystal latticeHeating40 000 V8000°C

2 mL

Mass of different elements

Light decomposition:wavelength → ray position

Ray intensity → electric current

Range: 1-1000 ppm

Sample



AluminumBariumLeadBoron

ChromiumIron

PotassiumCalciumCopperLithium

VanadiumTungsten

Detectable elements:

MagnesiumMolybdenum

SodiumNickel

PhosphorusSilicon

ZincTin

SilverTitanium



Analysis of several “normal” samples of lubricant

Average + standard deviation



Source: https://www.machinerylubrication.com/Read/296/grease-analysis

OK or slightly increased Increased ExtremeHigh



IF calcium and silicon levels are INCREASED to EXTREME

Pollution with lime and dust

IF copper, lead and tin levels are INCREASED to EXTREME

Abrasion

Iron levels

To be coupled with PQI results


Troubleshooting: Analysis of the «black, greasymaterial»IF PQI is EXTREME

Material fatigue

IF PQI is HIGH and iron levels are OK

Acute wear

IF both PQI and iron levels are INCREASED or HIGH

Normal wear (depending on lifetime)

IF PQI is OK and iron levels are INCREASED or HIGH

Corrosion (rust is not magnetizable)


Troubleshooting: ConclusionsCorrosion:Most likely comes from sealing problemsBatch analysis should be conducted to assess API pollution

Material fatigue:Most likely comes from a mechanical problemPossible causes include overload of the centrifuge, faulty components, faulty design, …Further investigations should be made and the sealings should be checked

Abrasion:Most likely comes from lack of lubricant or use of the wrong lubricantThe rotor components should be replaced but the batch should be intactNormal wear:An external shock or low quality steel (air bubble) could explain the hair crackThe rotor components should be replaced but the batch should be intact


What are key considerations you should focus on as acontract lab?


Troubleshooting

Scientific

Verifying and, if possible, cross-validating experiments

Accuracy

Standard procedure

Human

Discretion


Provocation: excitation of the sample by applying a form of energy

Reaction: interaction of sample with energy or return tothe ground state

Detection: change caused by the sample


General Characterization of Analytical Methods

Provocation Reaction Detection

Source: Lecture Script Analytical Chemistry I + II, Prof. Dr. Detlef Günther, Dr. Peter Lienemann, Beat Aeschlimann, Gisela H. Fontaine, Daniel A. Frick


FAAS GFAAS ICP-AES ICP-MS LIBS LA-ICP-MS

Sample liquid liquid liquid liquid solid solid

Limit of detection 0.1 ppm 0.1 ppb 0.001 - 0.1 ppm

ppt - ppb

Precision 1 % 3 % 1 - 2 % 1 %

Linear dynamicmeasuring range

3* 3* 4 - 5* 9*

Amount ofsample

ml μl ml ml

Costs $ $$ $$ - $$$ $$$

Personnelrequisition

low medium medium high

Sample throughput

slow very slow fast fast


Overview of Methods

FAAS: Flame Atomic Absorption SpectroscopyGFAAS: Graphite Furnace Atomic Absorption SpectroscopyICP-AES: Inductively Coupled Plasma Atomic Emission Spectroscopy

ICP-MS: Inductively Coupled Plasma Mass SpectrometryLIBS: Laser Induced Breakdown SpectroscopyLA-ICP-MS: Laser Ablation Inductively Coupled Plasma Mass Spectrometry

•Decadic orders of magnitude

Source: N. Lewen, J. Pharmaceut. Biomed., 55 (2011)


Nature of the sample matrix Analytical instrumentation available Amount of sample material available Desired analytes Desired method sensitivity Speed of analysis


Choice of Method



Schematic ICP-MS

Source: https://www.researchgate.net/figure/Schematic-of-an-Inductively-Coupled-Plasma-Mass-Spectrometer-ICP-MS_fig5_44226526


Different possibilities: Concentric Meinhard nebulizer Cross-flow nebulizer Babington nebulizer V-Groove nebulizer Sharp/GemCone/Burgener nebulizer Microconcentric/Direct injection nebulizer Ultrasonic nebulizer


ICP-MS: Nebulizer



Nebulizer gas flows around the sample capillary, whose end points to the conic top, generating small droplets


Nebulizer: Concentric Meinhard Nebulizer



Stability of aerosol yield Size distibution of the droplets Nebulizing efficiency Transport yield Washing out time Memory effect


Nebulizer: Things to be aware of



Scott chamber Cyclone chamber

The gas stream carrying the droplets is forced to make a abrupt change of direction

Only the small droplets can follow The larger droplets hit the wall and are removed from the

gas stream


ICP-MS: Spray Chamber



ICP-MS: Cyclone Spray Chamber

to ICP

sample

argonwaste

large droplets

small droplets



Plasma is created in the torch by an RF generator Torch consists of three concentric tubes: Injector tube: transport of the sample into the plasma Plasma/Intermediate gas: maintains plasma Cooling gas: avoids melting of the torch due to the high

temperature of the plasma (5000 – 8000 K) High temperature of plasma leads to formation of ions


ICP-MS: Torch



ICP-MS: Torch

Source: https://www.researchgate.net/figure/Fassel-type-torch-that-is-typically-used-in-MC-ICP-MS-Approximate-Ar-fl-ow-rates-for-the_fig2_254276358


Transfer of ions into vacuum (required for MS) Sampler cone (1 mm hole) Skimmer cone (0.4 mm hole)

Ion optics Extraction of a beam of ions and focussing it to the mass analyzer Separation from UV photons, energetic neutrals and other solid

particles carried into the instrument by the ICP


ICP-MS: Trasfer to Vaccum and Ion Optics



ICP-MS: Trasfer to Vaccum and Ion Optics

from ICP

cones

ion optics

vacuum pumps

quadrupole

Source: https://www.researchgate.net/figure/Schematic-of-an-Inductively-Coupled-Plasma-Mass-Spectrometer-ICP-MS_fig5_44226526


Quadrupole MS Sector field MS Time of flight MS


ICP-MS: Mass Spectrometry



Photomultiplier Faraday cup Daly detector


ICP-MS: Detection



External calibration Standard addition


ICP-MS: Quantification

Source: https://slideplayer.com/slide/2633911/ Source: https://en.wikipedia.org/wiki/Standard_addition


Polyatomic interferences: combination of two or moreisotopes from different elements, which usually occur inthe athmospheric plasma

Isobaric interferences: different elements whose isotopesshare a common mass


ICP-MS: Interferences



ICP-MS: Isotope Table Source: Lecture Script Analytical Chemistry I + II, Prof. Dr. Detlef Günther, Dr. Peter Lienemann, Beat Aeschlimann, Gisela H. Fontaine, Daniel A. Frick


However, in the overall production process of an API, there might be a range ofsources for “elemental impurities” which need to be controlled.


Routine AnalysisA crack in high quality, well-maintained equipment is something, which wouldusually not occur.

Source: http://www.socosur.eu

The International Conference on harmonization of technical requirements forregistration of pharmaceuticals for Human use (ICH) has issued guidelines fordealing with “elemental impurities”, referred to as ICH Q3D.


What are “elemental impurities” according to ICH Q3D? Metallic contaminations in drug products The ICH categorized the various elemental impurities infive different classifications: 1, 2A, 2B, 3 and others


Routine Analysis: Nature of ElementalImpurities

Source: International Conference on harmonization of technical requirements for registration of pharmaceuticals for human useICH HARMONISED GUIDELINE, GUIDELINE FOR ELEMENTAL IMPURITIES Q3D


Class Elements1 As, Cd, Pb, Hg2A Co, Ni, V2B Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, Tl3 Ba, Cr, Cu, Li, Mo, Sb, SnOther elements Al, B, Ca, Fe, K, Mg, Mn, Na, W, Zn


Routine Analysis: Classification



Routine Analysis: Origin of Elemental Impurities

*see Good Manufacturing Practices (GMP) **see Water Quality Requirements

What might be sources of elemental impurities in aproduction process?



Routine Analysis: Potential Sources

Manufacturing equipmentNickel, cobalt, vanadium, molybdenum, chromium, and copper from Hastelloy and stainless-steel alloys

Processing aids/inorganic reagentsProcessing aids such as charcoal, silica, celite, and darco, and inorganic reagents such as sodium chloride, magnesium sulfate, and sodium sulfate

Metal catalystsPalladium and platinum

Source: http://www.pharmtech.com/implementation-ich-q3d-elemental-impurities-guideline-challenges-and-opportunities


If you had to estimate to which extent they might come outand how this could be controlled, how would you set up arisk assessment?


Routine Analysis: Detection


Source: http://www.pharmtech.com/implementation-ich-q3d-elemental-impurities-guideline-challenges-and-opportunities


If you needed to analyse the Class 1, Class 2B elementsplus the used catalyst Pd for your customer in a drugproduct (tablet), which is prescribed with a max. daily doseof 2 g per day, which method/s would you suggest foranalysis?


Routine Analysis


Determining the target limit concentration for the analysis:



: permitted concentration limit (μg/g)

: Permitted Daily Exposure (μg/day)

: Recommended Daily Intake (2g/day)

Cl Permitted concentration limit (μg/g)

PDE Permitted daily exposure (μg/day)

DI Recommended daily intake (g/day)


Routine Analysis: DetectionThese are the PDEs for elemental impurities as recommended by the ICH

Source: International Conference onharmonization of technicalrequirements for registration ofpharmaceuticals for human useICH HARMONISED GUIDELINE,GUIDELINE FOR ELEMENTALIMPURITIES Q3D



Element Class Oral PDE (μg/day)

Cl (μg/g)

Cd, Pb 1 5 2.5As 1 15 7.5Hg 1 30 15Tl 2B 8 4Au, Pd, Ir, Os, Rh, Ru, Pt

2B 100 50

Se, Ag 2B 150 75

Determining target concentrations to analyze:• Classes 1 and 2B only• Oral ingestion (tablet)• Daily intake: 2g/day


Routine Analysis: Method

Inductively coupled plasma mass spectrometry (ICP-MS)

Advantages Inconvenientsspeed costprecision possible interferences with

other elementssensitivity easy contamination


Routine Analysis: Method

Source: Reddy et al. , Biomedical and Pharmaceutical Applications of Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), Drug discovery: From concept to market, 2017


What would be a suitable sample preparation? Whichconsiderations would be different for Tablet A and B?


Routine Analysis

Tablet A Tablet BAPI APIMicrocrystalline cellulose Microcrystalline celluloseHypromellose HypromelloseLactose SorbitolCrospovidone GelatineMagnesium stearateTitanium dioxide


Direct Dilution Acid Digestion Solid SampleUltra-high purity solventsrequired

Ultra-high purity acids required No sample preparation needed

Open vessel vs. closed vessel

Microwave assisted

Hot plate

HNO3, HCl, H2SO4, HF, H2O2


Sample Preparation



What would be a suitable sample preparation? Whichconsiderations would be different for Tablet A and B?

Tablet B: all components organic Tablet A: contains inorganic component (titanium dioxide)

Tablet B: direct dilution or acid digestion Tablet A: acid digestion in a closed vessel (due to Hg)


Routine Analysis


If your customer wanted to implement analysis of those elements for releaseanalysis, how would you ensure that the method is “valid” to analyse them at thislevel – in compliance with quality standard GMP (good manufacturing practice)?

Precision Accuracy Analytical procedure (SOP) Sensitivity, limit of detection Specificity Repeatability Robustness


Routine Analysis


If your customer wanted to implement analysis of those elements for releaseanalysis, how would you ensure that the method is “valid” to analyse them at thislevel – in compliance with quality standard GMP (good manufacturing practice)?

Demonstration of the lack of spectral interferences Demonstrate adequate recovery of analytes Demonstration of precision by determination of RSD Standard addition to demonstrate accuracy of method and adequacy of spikerecoveries Robustness of method by multiple day, multiple analyte and/or multipleinstrument verification of results


Routine Analysis



Thanks for your attention!

Are there any questions?

trace element analysis in pharmaceutical products

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