Total Solutions for Pharma Impurity Analysis

Liw Wan Tung

Asst. Market Manager (Bio/Pharma) | EXPERT Centre
Shimadzu (Asia Pacific) Pte Ltd

21st August 2023

Specialised Pharma Segments

Drug Discovery/ Research and Impurity Purification QAQC Testing

Medicinal Chemistry Development (R&D) Profiling Solution Hardware + Automation
Hardware Hardware Hardware Hardware Advanced i-Series
Preparative LC + LH-40 Nexera series N-series + LCMS-2050 N-series + LCMS-2050 Nexera series
Analytical SFC/Prep SFC Smart Automation Kit LC-MS TQ Analytical SFC/Prep SFC Software
HS-GC, GCMS-TQ
Software Software Software Analytical Intelligence
Software Advanced Algorithm
OpenSolution, ASAPrep, LabSolutions MD, OpenSolution,
LabSolutions CS,
Analytical Intelligence ASAPrep
LabSolutions Insight

Informatics • LabSolutions CS • Empower • Chromeleon • LabSolutions BiX • LIMS

Solutions Connectivity Connectivity eDashboard
Ethylene Glycol (EG)/Diethylene Glycol (DEG) in Medicinal Syrup
Year 2022

Year 2016

Pharma Impurity is ongoing

pressing issues that needs to be
addressed seriously
Pharmaceutical Impurities

Organic Residual Elemental

Impurities Solvent Impurities

Impurities Genotoxic
From Packaging Impurities
4
Organic Impurity Analysis (Related Substances)

• Nexera-i MT Method Transfer System:

enables both HPLC and UHPLC analysis

• Allows the migration between conventional

and high speed analysis within a single
system.

• Features Dual Flow Lines Simplify the

Process of Migrating Methods

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 AI and Automation Improve Lab Efficiency
Auto pumping in optimal flow rate Improve column
Auto-check of system condition (FlowPilot function), ClickTek in Nexis GC lifetime

Auto-purge of pump and autosampler

Start of analysis

Preparation

Auto-start-up at set time Auto-diagnostics and Auto-

Analysis recovery
Processing
Improve work
efficiency

Auto-flush of used flow line

Energy saving
Auto-shutdown after analysis
Auto-processing
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Residual Solvents

• Volatile organic compounds used in or generated from the manufacture of drug

substances, pharmaceutical additives, or drug products.
• Strictly controlled according to risk classifications from Class 1 to Class 3, which are
based on the risk to human health.

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 Residual Solvents

• Headspace GC methods specified in the USP (U.S. Pharmacopeia), General

Chapters <467> Residual Solvents* are commonly used for analysis of residual
solvents.

*https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc-467-residual-solvents-ira-20190927.pdf
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Class 1 Residual Solvents

*Procedure A requires that the S/N ratio

obtained to be 5 or higher

At Maximum Permissible Limits

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 Class 2A and 2B Residual solvents

*Procedure A requires resolution for acetonitrile

and methylene chloride to be 1.0 or greater

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11
Current Nitrosamine Impurities Checked in Pharma

List of Nitrosamine
List of API and Drug Products
impurities

NDMA Valsartan Ranitidine Metformin

NDEA Irbesartan Nizatidine
NEIPA Losartan Famotidine
NDIPA Olmesartan
NDBA Telmisartan
Pioglitazone
NMBA Candesartan
Cimetidine
NDPA Azilsartan
NMPrZ Rifampin
CPNP Rifapentine

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Nitrosamine USFDA Regulation

Control_of_Nitrosamine_Impurities_in Human_Drugs_Guidance_for_Industry
For drug products with an MDD of less than 880 mg/day, a recommended limit for
total nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered
acceptable. If nitrosamines without published AI limits are found in drug products,
manufacturers should use the approach outlined in ICH M7(R1) to determine the risk
associated with the nitrosamine and contact the Agency about the acceptability of any
proposed limit.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-
human-drugs
USP <1469> Analytical Methods for NSA Impurities

A variety of analytical procedure for Nitrosamine determination in USP <1469>

Procedure 1 Procedure 2 Procedure 3 Procedure 4
No. of Nitrosamine NDEA, NDMA, NIPEA, NDEA, NDMA, NIPEA, NDEA, NDMA, NIPEA, NDEA, NDMA, NIPEA,
NDIPA, NMBA, NDBA NDIPA NDIPA, NMBA, NDBA NDIPA, NMBA, NDBA

Suspension in Extraction by water with Extraction by methylene

Sample preparation Extraction by Methanol
Acetonitrile 1% formic acid chloride

Separation LC GC LC GC

Sample introduction Injection Headspace Injection Direct injection

Ionization ESI EI APCI EI

Detector HRMS MS (QQQ) MS (QQQ) MS (QQQ)
MS scan mode SIM, PRM (MS) MRM MRM MRM
Use of isotope-labeled
No Yes Yes Yes
internal standard
Quantitation Single standard Single standard Calibration curve Calibration curve
The UFMS Approach for Nitrosamine Analysis

Sartans
NMBA NDMA NDEA NIPEA NDIPA NDBA

Liq - GCMSMS
HS - GCMS
NX

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GCMS-TQ8050 NX
Enhanced Noise Reduction A Brand-New Analytical
• Quadrupole pre-rods Experience
• Overdrive lens • ClickTek tool-free glass
• Shielded detector insert replacement
• Touch screen navigation
• A brighter oven
• Active time management
Highest Capacity
Vacuum Pump
• Twinline MS support Constant Linear Velocity
• Compatible for He, H2, Flow Control Mode
and N2 carrier gas
• Shimadzu proprietary
• Reduced contamination
• Seamless method transfer
(MS & other GC detectors)
• Universal from any makes
 NSA Application notes I GCMS
• 7 nitrosamine impurities with GCMS-TQ direct and HS
injection (USP1469 procedure 2 & 4) in single method
• Metformin analysis with 5 nitrosamine impurities method
GCMS-TQ and HS direct injection (EDQM 2.5.42 procedure C)
Dynamic headspace mode, outperforms the current
regulatory limits, achieves 2.5 to 20 times higher sensitivity
compared to static headspace mode
• Highly efficient detector and superior noise reduction
technology; enhance sensitivity and enables trace levels
quantitation
UFMS Measurement of 24 NSA using GCMS-TQ8040 NX

Shimadzu Group PowerPoint Template 18

The UFMS Approach for NSA Analysis

Sartans
NMBA NDMA NDEA NIPEA NDIPA NDBA

Liq - GCMSMS
HS - GCMS
NX

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LC-MS Technology

What is Liquid Chromatography – Mass Spectrometry (LCMS)

1. LC – Separation of compounds based on their physical and chemical properties
1.86e7

Detection

1 2 3 4 5 6 7 8 9 10 11
RT (min)

2. MS – Determination of mass and charge of molecules

+ +2
361.14134

+2 + 242.08473

+3 5.0e5 360.13370

+ +2 4.0e5

+ 398.09374

3.0e5
+2
+2 + +3 2.0e5
212.12783
344.14248

+2 + 210.11230
243.08755
268.05371
341.11900

399.09666
1.0e5
151.03194 310.15467 322.02916 363.13810
417.20259
195.12495 213.13122
150.09071 153.02373 269.05686 456.14945

Molecular Weight 0.0e0

100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475
m/z
LCMS - Powerful Pharma Impurity Analysis Solution

Versatile Fast
o Monitor large panel of diverse o Monitor all targets in the
compounds shortest time
o One analysis to cover all; à high throughput
no additional analysis required à time & cost saving
à time & cost saving

Robust & Reliable Sensitive & Accurate

o Tolerates complex matrix o Low matrix impact
o Less maintenance and o High linearity and low
down-time LOD/LOQs
à time & cost saving à future ready

Qualitative Quantitative
o Screen and identify non- o Surpass regulatory
regulated compounds requirements and determine
àfuture ready maximum residue amount
à future ready
NSA Application I LCMS
Nitrosamines by LCMS-TQ
• USP 1469 has been published
• LCMS is required for procedure 1 and 3 as per analysis
methods of USP 1469

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NSA in Metformin Tablets I LCMS

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Market Requirements for NDSRI

vLCMS became a Pharma QAQC tool nowadays, because of stringent regulation.

vAs per the risk assessment, the NSA must be checked in various stages, API and Formulation R&D, QC plants, In-process,
Cleaning validations and stability lab etc.
vFor every molecule NSA assessment is mandatory for DMF (Drug master filing).

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Pharma Impurities NDSRI: Azido and Tetrazole

Shimadzu Ready Solutions for

Azido and Tetrazole
Nitrosamine Drug Substance-
Related Impurities (NDSRI)
by LCMS-TQ
LC-MS/MS Method for Detection and Quantitation of Azido Impurities in Irbesartan Drug Substance

https://shimadzugroup.sharepoint.com/sites/gcs/an_sales/Literature/Distributor/
Chromatography/LCMS/an_09-ssk-011-en.pdf#search=tetrazole
Solutions for NDSRI Analysis

HS - GCMS GC-MS/MS LCMSMS LC - QTOF

Target NDMA, NDEA, NDMA, NDEA, NDBA, NMBA, NDEA, NDMA, NMBA, NDEA, NDMA,
compound NDIPA, NEIPA NMEA, NDPA, NPYR, NIEPA, NDIPA, NDBA NIEPA, NDIPA, NDBA
NPiP, NEIPA, NDIPA,
NPir, NMor, NDPhA
Sample Solid & liquid Extracted liquid Liquid (dissolved) Liquid (dissolved)
Advantage Minimal sample Wide range analysis Short analysis time Untargeted analysis,
preparation High Resolution MS
and mass accuracy
Extractables and Leachables (E&L)

HS Trap - GCMS TD - GCMS QTOF (LCMS-9050)

Target compound High volatile Semi volatile Semi volatile

Sample Large volume Small volume Large volume

Solid & liquid Solid Liquid (dissolved)
Advantage Other applications No septum bleed High Resolution MS and
Residual solvent & mass accuracy
nitrosamines
 Elemental Impurities I ICPMS-2030

ICPMS-2030

ICPMS
Target compound 24 elemental impurities as specified in the USP 232-233 / ICH Q3D
Samples All types of formulations / raw materials
Liquid (dissolved / digested)
Smart features Ø Laboratory networking with FDA 21 CFR Part 11 compliance
Ø Industry unique features like Method Development Assistant, Diagnosis Assistant
Ø Quick screening capability using Total Mass Profile feature
Total Solution for Pharma Impurity Analysis
Shimadzu Total MS Solution for Pharmaceutical Impurity & Nitrosamine Analysis

NX
Genotoxic
Impurities

Organic NDSRI in
Impurities Sartan

Pharmaceuti
cal LCMS-9050
Impurities
EG/DEG
Residual in
Solvents Mecidinal
Nexis GC-2030 + HS-20 Syrup
Impurity
from
Packagin
g
LabSolutions CS I Backbone of Data Compliance – Accuracy, Consistency, Traceability

Integrity

Automation

Efficiency

• Data Management and Compliance “ Pharma Manufacturers need robust and reliable
• Automating operational workflows data management systems to guarantee and
• Increased efficiency and productivity demonstrate regulatory compliance ”
LabSolutions Analytics – Unique Features

Lab Analytics Instrument Planner BiX Live

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LabSolutions BiX I Pharma Specific New Features – Overall features
Product Wise Efficiency Calculation – Reports for Management Review
Date Range Selection

Product(s) Selection

Products Wise Batches

User Wise Batch List

Efficiency Calculation
by 16H / 24H
iLIMS I Pharma QC Ready Application for Sample Management

Shimadzu’s Unique Solutions for MSMEs

• Sample Manager I
Instrument Manager I
Instrument Interface I

• 40-Days Implementation I
Perfect solution for Pharma-QC I

LabSolutions CS Seamless Integration LIMS

Total Compliance Solutions Powered by Living Lab

Living Laboratory Integrates All Of Our Technologies Including Living Instruments™ Together With LabSolutions To
Create A Thriving Shimadzu Ecosystem
5 Specialised Pharma Segments

Drug Discovery/ Drug Development Formulation Preclinical and Quality Testing

Medicinal Chemistry Pharma R&D Development & Clinical Trial Hardware
Hardware Hardware Impurity Profiling Hardware Ai-series, Nexis GC & HS,
Preparative LC + LH-40 N-series+pHM-40, AMD
N-series IRXross, TOC, UV-1900i
Analytical SFC/Prep SFC LCMS-SQ, TQ Hardware
LCMS-2050, LCMS TQ Software
Smart Automation Kit N-series + LCMS TQ
Software LabSolutions CS, AI, WFA
Software GCMS-TQ, Q-TOF Software
OpenSolution, ASAPrep, MPM, FlowPilot, Auto-
Purification Solution LabSolutions MD i-PeakTracer Software LabSolutions Insight
Analytical Intelligence (AI) LabSolutions Insight Recovery
i-PDeA, i-DReC, ASP, APF, i-PeakFinder
Peakintelligence i-PDeA, i-DReC

• LabSolutions CS • Empower • Chromeleon • LabSolutions BiX • LIMS

Informatics Workflows Connectivity Connectivity eDashboard
Network