Loading…

Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active p...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmaceutical and biomedical analysis 2009-09, Vol.50 (2), p.144-150
Main Authors: Liu, David Q., Chen, Ted K., McGuire, Michael A., Kord, Alireza S.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13
cites cdi_FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13
container_end_page 150
container_issue 2
container_start_page 144
container_title Journal of pharmaceutical and biomedical analysis
container_volume 50
creator Liu, David Q.
Chen, Ted K.
McGuire, Michael A.
Kord, Alireza S.
description Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.
doi_str_mv 10.1016/j.jpba.2009.04.002
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_20077707</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0731708509002192</els_id><sourcerecordid>20077707</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13</originalsourceid><addsrcrecordid>eNp9kM2OFCEURonROG3rC7gwbHRXJdBVRZO4mUz8SyZxM5PMjtCXyzSdKiiBMrZPP3S6ozs33AXn-y4cQt5y1nLGh4-H9jDvTCsYUy3rWsbEM7LiW7lpxNA9PCcrJje8kWzbX5FXOR8YYz1X3UtyVU8heT-siL4OZjwWD2akEENJcaTR0UcMscTfHqif5iX54jFTH2jZI53Nnzib4Hd0f7Qpwn6MyVukkwmLM1AqHh7pXG8w59fkhTNjxjeXuSb3Xz7f3Xxrbn98_X5zfdtAx_vSGCEUl2qLzgIyZxlCpwBRWegRegduqyQfbC-tMhYALXAhOqGkYoLt-GZNPpx7696fC-aiJ58Bx9EEjEvWVZKUsgpZE3EGIcWcEzo9Jz-ZdNSc6ZNWfdAnraeE0qzTVWsNvbu0L7sJ7b_IxWMF3l8Ak6tKl0wAn_9ygg9d7VaV-3TmsLr45THpDB5D_Y9PCEXb6P_3jifTN5kf</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20077707</pqid></control><display><type>article</type><title>Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process</title><source>ScienceDirect Freedom Collection</source><creator>Liu, David Q. ; Chen, Ted K. ; McGuire, Michael A. ; Kord, Alireza S.</creator><creatorcontrib>Liu, David Q. ; Chen, Ted K. ; McGuire, Michael A. ; Kord, Alireza S.</creatorcontrib><description>Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.</description><identifier>ISSN: 0731-7085</identifier><identifier>EISSN: 1873-264X</identifier><identifier>DOI: 10.1016/j.jpba.2009.04.002</identifier><identifier>PMID: 19427156</identifier><identifier>CODEN: JPBADA</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Analysis ; Analytical control strategy ; Analytical, structural and metabolic biochemistry ; Biological and medical sciences ; Chemistry, Pharmaceutical ; Chromatography, Liquid ; Drug Contamination ; Fundamental and applied biological sciences. Psychology ; General pharmacology ; Genotoxic impurity ; Mass Spectrometry ; Medical sciences ; Mutagens - analysis ; Pazopanib hydrochloride ; Pharmacology. Drug treatments ; Pyrimidines - chemistry ; Spectrophotometry, Ultraviolet ; Spiking/purging ; Sulfonamides - chemistry ; Trace analysis</subject><ispartof>Journal of pharmaceutical and biomedical analysis, 2009-09, Vol.50 (2), p.144-150</ispartof><rights>2009 Elsevier B.V.</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13</citedby><cites>FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=21641019$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19427156$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, David Q.</creatorcontrib><creatorcontrib>Chen, Ted K.</creatorcontrib><creatorcontrib>McGuire, Michael A.</creatorcontrib><creatorcontrib>Kord, Alireza S.</creatorcontrib><title>Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process</title><title>Journal of pharmaceutical and biomedical analysis</title><addtitle>J Pharm Biomed Anal</addtitle><description>Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.</description><subject>Analysis</subject><subject>Analytical control strategy</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Biological and medical sciences</subject><subject>Chemistry, Pharmaceutical</subject><subject>Chromatography, Liquid</subject><subject>Drug Contamination</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>General pharmacology</subject><subject>Genotoxic impurity</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Mutagens - analysis</subject><subject>Pazopanib hydrochloride</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrimidines - chemistry</subject><subject>Spectrophotometry, Ultraviolet</subject><subject>Spiking/purging</subject><subject>Sulfonamides - chemistry</subject><subject>Trace analysis</subject><issn>0731-7085</issn><issn>1873-264X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNp9kM2OFCEURonROG3rC7gwbHRXJdBVRZO4mUz8SyZxM5PMjtCXyzSdKiiBMrZPP3S6ozs33AXn-y4cQt5y1nLGh4-H9jDvTCsYUy3rWsbEM7LiW7lpxNA9PCcrJje8kWzbX5FXOR8YYz1X3UtyVU8heT-siL4OZjwWD2akEENJcaTR0UcMscTfHqif5iX54jFTH2jZI53Nnzib4Hd0f7Qpwn6MyVukkwmLM1AqHh7pXG8w59fkhTNjxjeXuSb3Xz7f3Xxrbn98_X5zfdtAx_vSGCEUl2qLzgIyZxlCpwBRWegRegduqyQfbC-tMhYALXAhOqGkYoLt-GZNPpx7696fC-aiJ58Bx9EEjEvWVZKUsgpZE3EGIcWcEzo9Jz-ZdNSc6ZNWfdAnraeE0qzTVWsNvbu0L7sJ7b_IxWMF3l8Ak6tKl0wAn_9ygg9d7VaV-3TmsLr45THpDB5D_Y9PCEXb6P_3jifTN5kf</recordid><startdate>20090908</startdate><enddate>20090908</enddate><creator>Liu, David Q.</creator><creator>Chen, Ted K.</creator><creator>McGuire, Michael A.</creator><creator>Kord, Alireza S.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>F1W</scope><scope>FR3</scope><scope>H99</scope><scope>L.F</scope><scope>L.G</scope><scope>P64</scope></search><sort><creationdate>20090908</creationdate><title>Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process</title><author>Liu, David Q. ; Chen, Ted K. ; McGuire, Michael A. ; Kord, Alireza S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Analysis</topic><topic>Analytical control strategy</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Biological and medical sciences</topic><topic>Chemistry, Pharmaceutical</topic><topic>Chromatography, Liquid</topic><topic>Drug Contamination</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>General pharmacology</topic><topic>Genotoxic impurity</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Mutagens - analysis</topic><topic>Pazopanib hydrochloride</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrimidines - chemistry</topic><topic>Spectrophotometry, Ultraviolet</topic><topic>Spiking/purging</topic><topic>Sulfonamides - chemistry</topic><topic>Trace analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, David Q.</creatorcontrib><creatorcontrib>Chen, Ted K.</creatorcontrib><creatorcontrib>McGuire, Michael A.</creatorcontrib><creatorcontrib>Kord, Alireza S.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Engineering Research Database</collection><collection>ASFA: Marine Biotechnology Abstracts</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) Marine Biotechnology Abstracts</collection><collection>Aquatic Science &amp; Fisheries Abstracts (ASFA) Professional</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, David Q.</au><au>Chen, Ted K.</au><au>McGuire, Michael A.</au><au>Kord, Alireza S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process</atitle><jtitle>Journal of pharmaceutical and biomedical analysis</jtitle><addtitle>J Pharm Biomed Anal</addtitle><date>2009-09-08</date><risdate>2009</risdate><volume>50</volume><issue>2</issue><spage>144</spage><epage>150</epage><pages>144-150</pages><issn>0731-7085</issn><eissn>1873-264X</eissn><coden>JPBADA</coden><abstract>Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>19427156</pmid><doi>10.1016/j.jpba.2009.04.002</doi><tpages>7</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0731-7085
ispartof Journal of pharmaceutical and biomedical analysis, 2009-09, Vol.50 (2), p.144-150
issn 0731-7085
1873-264X
language eng
recordid cdi_proquest_miscellaneous_20077707
source ScienceDirect Freedom Collection
subjects Analysis
Analytical control strategy
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Chemistry, Pharmaceutical
Chromatography, Liquid
Drug Contamination
Fundamental and applied biological sciences. Psychology
General pharmacology
Genotoxic impurity
Mass Spectrometry
Medical sciences
Mutagens - analysis
Pazopanib hydrochloride
Pharmacology. Drug treatments
Pyrimidines - chemistry
Spectrophotometry, Ultraviolet
Spiking/purging
Sulfonamides - chemistry
Trace analysis
title Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T17%3A04%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Analytical%20control%20of%20genotoxic%20impurities%20in%20the%20pazopanib%20hydrochloride%20manufacturing%20process&rft.jtitle=Journal%20of%20pharmaceutical%20and%20biomedical%20analysis&rft.au=Liu,%20David%20Q.&rft.date=2009-09-08&rft.volume=50&rft.issue=2&rft.spage=144&rft.epage=150&rft.pages=144-150&rft.issn=0731-7085&rft.eissn=1873-264X&rft.coden=JPBADA&rft_id=info:doi/10.1016/j.jpba.2009.04.002&rft_dat=%3Cproquest_cross%3E20077707%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c415t-a2291798efdce0fd0ec49cee9dc5ec5fcf89716d57d9adccedc12242979020b13%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=20077707&rft_id=info:pmid/19427156&rfr_iscdi=true