Pharmaceutical Technology Europe - March 2012 - (Page 13)

Evaluating impurities in drugs — Part II Controlling and monitoring impurities in APIs and finished drug products is a crucial issue in drug development and manufacturing. In Part II of this article, the authors examine impurities from chiral molecules, polymorphic contaminants and genotoxic impurities. Part I can be accessed at PharmTech.com/impuritiespart1. Chiral impurities Impurities can be present in the enantiomers of chiral compounds. Differences in pharmacological and toxicological profiles have been observed with chiral impurities in vivo, suggesting that chiral impurities should be monitored carefully. Although development of chiral drugs as single stereoisomers is a preferred approach, consideration must be given to unwanted stereoisomers, which may be present as impurities or degradants in the drug substance or drug product or generated through metabolism in biological systems. 2 SPECIAL FEATURE 11 PARAMETRIC RELEASE Guidelines on the development of chiral compounds are published by regulatory authorities worldwide, but they can be general and leave room for interpretation. Polymorphic impurities Polymorphism, the ability of a compound to exist in more than one crystalline form, affects the physical, chemical and biological properties of a compound in question. These properties may influence several issues in pharmaceutical systems, such as processing characteristics, drug stability and bioavailability. Demonstrating an understanding of the polymorphs in a given drug is an area of regulatory scrutiny in new drug applications. The International Conference on Harmonisation’s Q6A guideline, Specification: Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, outlines when and how polymorphic 7 REDUNDANT FILTRATION 12 COLUMN CRUNCH forms should be monitored and controlled. Exceptional case impurities When a new process is developed, such as to overcome patent issues, it generally begins with new key starting materials, intermediates, reagents or solvents that may react differently to give byproducts or process impurities. For example, in the synthesis of linezolid and pemetrexed disodium, several process impurities can be formed due to different process approaches. Genotoxic impurities There was no specific document on the control of genotoxic impurities before 2000, but ICH guidelines made passing references to compounds of unusual toxicity. Genotoxic impurities are chemical compounds that may be mutagenic and could potentially damage DNA. Non-monoalkylated agents are 8 NEWS BITES 13 PEER REVIEW classified as genotoxic due to the nature of the functional groups they possess and also of related aniline derivatives. Additionally, salt-forming steps can introduce genotoxic impurities. Some examples include the formation of methyl chloride as a side reaction of hydrochloric acid in methanol or esters of methanesulfonic acid as byproducts from the methanesulfonic acid saltformation step in alcohol-based solvents. Read the full text at: PharmTech.com/impuritiespart2 Kashyap R. Wadekar, Mitali Bhalme, S. Srinivasa Rao, K. Vigneshwar Reddy, L. Sampath Kumar, E. Balasubrahmanyam and Ponnaiah Ravi 9 BLOG 14 TOP TECH http://www.PharmTech.com/impuritiespart1 http://www.PharmTech.com/impuritiespart2

Table of Contents for the Digital Edition of Pharmaceutical Technology Europe - March 2012

Pharmaceutical Technology Europe - March 2012
Contents
Innovations, drivers and trends in adjuvant filtration
Focus: Redundant filtration
News Bites
Blogs Abridged
Interview: Parametric release and real-time release testing
Column Crunch: Counterfeits and outsourcing trends
Evaluating drug impurities
Top Tech

Pharmaceutical Technology Europe - March 2012