Handbook of Isolation and Characterization of Impurities in Pharmaceuticals

Front Cover
Academic Press, 2003 - Medical - 414 pages
2 Reviews
The United States Food and Drug Administration (FDA) and other regulatory bodies around the world require that impurities in drug substance and drug product levels recommended by the International Conference on Harmonisation (ICH) be isolated and characterized.

Identifying process-related impurities and degradation products also helps us to understand the production of impurities and assists in defining degradation mechanisms. When this process is performed at an early stage, there is ample time to address various aspects of drug development to prevent or control the production of impurities and degradation products well before the regulatory filing and thus assure production of a high-quality drug product.

This book, therefore, has been designed to meet the need for a reference text on the complex process of isolation and characterization of process-related (synthesis and formulation) impurities and degradation products to meet critical requlatory requirements.

It's objective is to provide guidance on isolating and characterizing impurities of pharmaceuticals such as drug candidates, drug substances, and drug products. The book outlines impurity identification processes and will be a key resource document for impurity analysis, isolation/synthesis, and characterization.

- Provides valuable information on isolation and characterization of impurities.
- Gives a regulatory perspective on the subject.
- Describes various considerations involved in meeting regulatory requirements.
- Discusses various sources of impurities and degredation products.
 

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Contents

Overview Isolation and Characterization
1
II Designations of Impurities
4
Regulatory Requirements
7
IV Sources of Impurities
8
V Analytical Method Development
14
VI Isolation Methods
18
VII Characterization Methods
20
VIM Case Studies
22
I Introduction
166
III LiquidLiquid Extraction LLE
174
IV Supercritical Fluid Extraction SPE
181
V Accelerated Solvent Extraction ASE
189
VI Centrifugation
194
VII Filtration
195
VIII Summary
199
Isolation Methods I ThinLayer Chromatography
203

IX Summary
24
Review of Regulatory Guidance on Impurities
27
II Types of ImpuritiesDrug Substance
28
III Role of Compendia
30
IV Role of Drug Master Files DMFType II and Impurities Evaluation
31
V Reference Standards for the Quantitation of Impurities and Analytical Procedures
32
VII Impurities in Drug Products
33
IX Impurities Quantitation PostApproval
36
References
37
Polymorphic and Solvatomorphic Impurities
39
II Xray Diffraction
40
III Thermal Methods of Analysis
44
IV Vibrational Spectroscopy
49
V SolidState Nuclear Magnetic Resonance Spectrometry
57
References
69
Impurities in Drug Products
75
II Water
76
III Peroxides
78
IV Aldehydes
79
V Metal Impurities
80
VII LeachablesExtractables
82
VIII Alcohols As Impurities
83
X Additives in Excipients
84
XI Final Observations
85
Strategies for Investigation and Control of Process and DegradationRelated
89
II Goals and Strategies
91
III ProcessRelated Impurities
95
IV DegradationRelated Impurities
102
V Summary and Conclusions
115
References
116
Reference Standards
119
II Definitions
120
Life Cycle
121
IV Governance
125
V Qualification Process
127
VI Summary
139
Sample Selection for Analytical Method Development
145
KPSS
147
IV Matrix Components
150
VI Purposeful Degradation Samples
152
VII Stability Samples
155
VIII PhaseSolubility Analysis
156
IX Sample Selection Strategies
159
X Summary
162
References
163
II TLC Applications in Pharmaceutical Industry
206
III TLC Method Development and Validation
207
IV Impurity Isolation and Characterization by TLC
221
References
228
Isolation Methods II Column Chromatography
231
II Background
232
III Stationary Phases
233
IV Equipment
237
V Screening
240
VI Development of Preparative Method
244
VII Scaleup of Preparative Method
246
VIII Summary
248
Mass Spectral Characterization
249
II Relevance of Impurity Characterization
252
III The Coupling of LiquidPhase Separations and Mass Spectrometers
259
IV Ion Formation
264
V Analyzers
273
VI Ion Structure Interrogation
277
VII Data Acquisition and Interpretation
282
VIII Applications
286
IX Conclusions
288
X Summary
289
References
290
NMR Characterization of Impurities
301
II Information Gathering
304
III Sample Preparation for NHR
305
IV Sample Preparation for LCNMR
307
V NMR Instrumentation
309
VI NMR Experiments
314
VII Choosing An Experiment Set
324
VIII Data Interpretation
325
IX Final Steps
334
X Summary
336
References
337
Hyphenated Characterization Techniques
341
II Experimental Examples
350
III Conclusions
356
References
357
Solving ImpurityDegradation Problems Case Studies
361
II Case Studies
368
III Summary and Conclusions
398
References
399
Index
401
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About the author (2003)

Satinder Ahuja earned his PhD in analytical chemistry from the University of the Sciences, Philadelphia. He worked for Novartis Corp. in various leadership positions for over 25 years while simultaneously teaching and guiding research as an adjunct professor at Pace University for over 10 years. As president of Ahuja Consulting, he advises on quality issues relating to chemicals/pharmaceuticals and water. Dr. Ahuja has published numerous papers and more than eighteen books. Two of his latest books are entitled "Water Reclamation and Sustainability" (Elsevier) and Comprehensive "Water Quality and Purification" (Elsevier). Others include "Monitoring Water Quality: Pollution Assessment, Analysis, and Remediation" (Elsevier, 2013); "Novel Solutions to Water Pollution" (ACS Symposium Volume, 2013); "Handbook of Water Purity and Quality" (Elsevier, 2009); and "Arsenic Contamination of Water: Mechanism, Analysis, and Remediation" (Wiley, 2008). A member of the executive committee of Rivers of the World Foundation (ROW), Dr. Ahuja is an expert on improving water quality and has organized numerous global symposia on this topic (American Chemical Society, UNESCO, etc.) In 2013, he gave a lecture on the nexus of food, energy, and water and chaired a symposium on the subject for the American Chemical Society meeting in New Orleans.

Dr. Karen Mills Alsante is a Senior Research Investigator in the Analytical Research & Development Department at Pfizer Groton Central Research. She worked as a Development Scientist in Groton Quality Operations for 3 years before moving to her current position in the Analytical Research & Development department in 1997. Over the past five years, Karen has established a Degredation Technology Group with the mission of gaining a better understanding of the chemical and physical stability of Pfizer drug substances and drug products at an earlier stage of the drug development process.

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