Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products

This paper outlines strategies in alignment with ICH M7 for systematically assessing the potential risk posed by mutagenic degradants in active pharmaceutical ingredients (API) and formulated products. A mutagen risk assessment (MRA) process that involves degradation should include results from focused drug substance and drug product stress testing experiments (e.g., at elevated temperature, a wide pH range in solution, oxidative, and photolytic stress) as well as accelerated and long-term stability studies in the solid-state. While the MRA may include hypothetical (theoretically predicted) degradation products from computer based and/or knowledge-based approaches, investigations for numerous hypothetical degradation products whose significance have not been verified experimentally should not be initiated based on these results alone. Drug substance and drug product stress (forced degradation) studies should be designed to generate a comprehensive range of potential degradants that encompass all degradati...

[1]  M. A. Ott,et al.  An expert system to predict the forced degradation of organic molecules. , 2013, Molecular pharmaceutics.

[2]  Karen M. Alsante,et al.  Stress Testing: A Predictive Tool , 2016 .

[3]  H. Gally,et al.  Overall impact of the regulatory requirements for genotoxic impurities on the drug development process. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[4]  Patrick Lukulay,et al.  Improved Protocol and Data Analysis for Accelerated Shelf-Life Estimation of Solid Dosage Forms , 2007, Pharmaceutical Research.

[5]  David L. Pole,et al.  Prediction of drug degradants using DELPHI: an expert system for focusing knowledge. , 2007 .

[6]  Steven W Baertschi,et al.  Implications of In-Use Photostability: Proposed Guidance for Photostability Testing and Labeling to Support the Administration of Photosensitive Pharmaceutical Products, Part 2: Topical Drug Product. , 2015, Journal of pharmaceutical sciences.

[7]  David Q. Liu,et al.  Recent advances in trace analysis of pharmaceutical genotoxic impurities. , 2010, Journal of pharmaceutical and biomedical analysis.

[8]  Lutz Müller,et al.  A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. , 2006, Regulatory toxicology and pharmacology : RTP.

[9]  Karen M. Alsante,et al.  Stress Testing: The Chemistry of Drug Degradation , 2016 .

[10]  Andrew Teasdale,et al.  Genotoxic Impurities: Strategies for Identification and Control , 2011 .

[11]  D. Brusick.  A perspective on testing of existing pharmaceutical excipients for genotoxic impurities. , 2009, Regulatory toxicology and pharmacology : RTP.

[12]  D. Elder,et al.  Analytical approaches for the detection of epoxides and hydroperoxides in active pharmaceutical ingredients, drug products and herbals. , 2010, Journal of pharmaceutical and biomedical analysis.

[13]  Karen M. Alsante,et al.  In silico prediction of pharmaceutical degradation pathways: a benchmarking study. , 2014, Molecular pharmaceutics.

[14]  Linda K Dow,et al.  The assessment of impurities for genotoxic potential and subsequent control in drug substance and drug product. , 2013, Journal of pharmaceutical sciences.

[15]  Nigel Greene,et al.  The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. , 2006, Regulatory toxicology and pharmacology : RTP.

[16]  Fran DeGrazio,et al.  Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products: An Overview of the PQRI Recommendations , 2008, Pharmaceutical Research.

[17]  Michael P. Ryan,et al.  Risk Assessment of Potentially Genotoxic Impurities within the Framework of Quality by Design , 2010 .

[18]  Neha Parashar,et al.  Forced degradation studies to assess the stability of drugs and products , 2013 .

[19]  Robert J. Timpano,et al.  N-methylation and N-formylation of a secondary amine drug (varenicline) in an osmotic tablet. , 2008, Journal of pharmaceutical sciences.

[20]  S. Baertschi.  Analytical methodologies for discovering and profiling degradation-related impurities , 2006 .

[21]  Sarfaraz Niazi,et al.  Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products , 2016, Handbook of Pharmaceutical Manufacturing Formulations, Second Edition.

[22]  Jinhua J. Song,et al.  Best Practices for Drug Substance Stress and Stability Studies During Early-Stage Development Part I—Conducting Drug Substance Solid Stress to Support Phase Ia Clinical Trials , 2012, Journal of Pharmaceutical Innovation.

[23]  N V V S S Raman,et al.  Strategies for the identification, control and determination of genotoxic impurities in drug substances: a pharmaceutical industry perspective. , 2011, Journal of pharmaceutical and biomedical analysis.

[24]  R. Adami,et al.  Accelerated aging: prediction of chemical stability of pharmaceuticals. , 2005, International journal of pharmaceutics.

[25]  D. Snodin,et al.  Guidelines and pharmacopoeial standards for pharmaceutical impurities: overview and critical assessment. , 2012, Regulatory toxicology and pharmacology : RTP.

[26]  Juan C. Scaiano,et al.  Modern Molecular Photochemistry of Organic Molecules , 1978 .

[27]  G. Boccardi.  Autoxidation of drugs: prediction of degradation impurities from results of reaction with radical chain initiators. , 1994, Farmaco.

[28]  D. Snodin.  Genotoxic Impurities: From Structural Alerts to Qualification , 2010 .

[29]  Patrick Sandra,et al.  Strategic Approaches to the Chromatographic Analysis of Genotoxic Impurities , 2011 .

[30]  Dan W. Reynolds,et al.  Available guidance and best practices for conducting force degradation studies , 2002 .

[31]  David K. Robbins,et al.  Risk Assessment of Genotoxic Impurities in Marketed Compounds Administered over a Short-Term Duration: Applications to Oncology Products and Implications for Impurity Control Limits , 2010 .

[32]  Sarfaraz Niazi.  - Impurities: Guideline for Residual Solvents , 2016 .

[33]  Karen M. Alsante,et al.  The role of degradant profiling in active pharmaceutical ingredients and drug products. , 2007, Advanced drug delivery reviews.

[34]  Steven W Baertschi,et al.  Implications of in-use photostability: proposed guidance for photostability testing and labeling to support the administration of photosensitive pharmaceutical products, part 1: drug products administered by injection. , 2013, Journal of pharmaceutical sciences.

[35]  Roger O McClellan,et al.  Development of safety qualification thresholds and their use in orally inhaled and nasal drug product evaluation. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  C. M. Won,et al.  Photolytic and oxidative degradation of an antiemetic agent, RG 12915 , 1995 .

[37]  E. Nelson,et al.  Solvent effects on the AIBN forced degradation of cumene: Implications for forced degradation practices. , 2009, Journal of pharmaceutical sciences.

[38]  T. McGovern,et al.  Regulation of genotoxic and carcinogenic impurities in drug substances and products , 2006 .

[39]  Derek Robinson,et al.  Control of Genotoxic Impurities in Active Pharmaceutical Ingredients: A Review and Perspective , 2010 .

[40]  Karen M. Alsante,et al.  A stress testing benchmarking study , 2003 .

[41]  David Q. Liu,et al.  Analytical challenges in stability testing for genotoxic impurities , 2013 .

[42]  Hui Xu,et al.  Evaluation of hydroperoxides in common pharmaceutical excipients. , 2007, Journal of pharmaceutical sciences.