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Tables of Contents for Analytical Chemistry in a Gmp Environment
Chapter/Section Title
Page #
Page Count
Contributors
xix
Foreword
xxi
Preface
xxiii
The Laboratory Analyst's Role in the Drug Development Process
1
30
Jonathan B. Crowther
William Lauwers
Sagar Adusumalli
Ponniah Shebagamurthi
Introduction
1
4
The Importance of Analytical Methodology in the Drug Development Process
1
1
Interdiscipline Use of Analytical Methodology
2
1
Phases of Drug Development
3
1
Introductory Summary
4
1
Requirements of an Analytical Methodology During the Drug Development Process Release and Stability
5
67
Introduction
5
1
Discovery Phase
6
1
Early Development
6
3
Final Development (Phase III)
9
63
The Analyst Role in Formulations Development
72
Overview
12
1
Analytical Testing in Formulations Development
13
1
Pharmaceutcal Excipients
13
1
Pharmaceutical Development Summary
13
2
Review of the Analyst Role in Pharmacokinetics, Toxicology, and Clinical Support
15
8
Introduction
15
1
Bioanalytical Considerations
15
3
Preclinical Pharmacokinetics/Pharmacodynamics
18
1
Preclinical Safety Studies
19
2
Mass Balance and Metabolism
21
1
Clinical Support
21
2
Stability Program in Pharmaceutical Industry
23
5
Introduction
23
1
Goals of the Stability Program
24
1
ICH Guidelines on Stability Testing of Drug Products
24
2
Stability Monitoring
26
1
Stability-Indicating Methods
26
1
Pharmaceutical Packaging and Stability
26
2
Stability Summary
28
1
Chapter Summary
28
3
References
29
2
Laboratory Controls and Compliance
31
18
Henry Avallone
Introduction
31
2
Laboratory Management
33
2
Management Responsibility
33
1
Training
34
1
Laboratory Controls
35
7
Laboratory Records
35
3
Out of Specification/Trend (OOS/OOT)
38
1
Laboratory Deviations/Nonconformances
39
2
Test Methods/Procedures/Specifications
41
1
Calibration and Maintenance
41
1
Laboratory Compliance
42
5
General Notices
42
1
Method Development
43
1
Method Validation
44
2
Method Transfer
46
1
Auditing the Laboratory
46
1
Use of Outside Testing Laboratories
47
1
Conclusion
47
2
References
47
2
The USP, ICH, and Other Compendial Methods
49
28
Jennifer G. Feldman
Introduction
49
1
USP/NF
49
7
Introduction
49
2
Organization/Overview
51
2
USP/NF and the FDA
53
1
FDA Requirements for Regulatory Submissions/Field Inspections
53
1
Analysis of Excipients/Raw Materials/Drug Substance/Drug Product
54
1
``Meets USP'' Labeling
54
1
Methodology
55
1
Accept/Reject Criteria
55
1
Validation
56
1
European, British, Japanese Pharmacopeias
56
3
EP, Third Edition
56
1
BP
57
1
JP, Thirteenth Edition
58
1
ICH Guideline
59
15
Introduction/Role of the Guidelines
59
1
Summary of the Guidelines
60
14
Conclusion
74
3
References
75
2
Statistics in the Pharmaceutical Analysis Laboratory
77
28
Alvin J. Melveger
Errors Associated with Making Measurements
78
1
Systemic Error
79
1
Random Error
79
1
Significant Figures and Rounding
79
5
Number of Significant Figures
79
3
Rounding
82
2
Some Definitions
84
7
Accuracy
84
1
Precision
85
1
Absolute Error
85
1
Relative Error
86
1
Mean
86
1
Average Deviation
86
1
Standard Deviation
87
1
Relative Standard Deviation
88
1
Comparison of Precision and Accuracy
88
1
Standard Error
89
2
Normal Distribution of Repeated Measurements
91
1
Student t Test
92
3
Application of t Test
93
2
Propagation of Uncertainty (Errors)
95
2
Addition and Subtraction of Uncertainties
95
1
Multiplication or Division of Uncertainties
96
1
Rejection of Outliners
97
1
Linear Regression Analysis
98
1
Quality Assurance/Control
99
3
Conclusion
102
3
References
102
3
Basic Analytical Operations and Solution Chemistry
105
44
Nicholas H. Snow
Wyatt R. Murphy, Jr.
Analytical Reagents
105
2
Sampling
107
5
Obtaining a Representative Sample
107
1
Preparing Samples for Analytical Methods
107
1
Weighting and Balances
108
2
Volumetric Glassware
110
1
Filtering
111
1
Chemical Equilibrium
112
8
Equilibrium Constants
112
2
Le Chatelier's Principle
114
2
Equilibrium as a Basis for Sample Pretreatment
116
4
Aqueous Solution Equilibria
120
4
Introduction
120
1
Acids and Bases
121
3
Reduction--Oxidation Equilibria
124
17
Introduction
124
17
Karl Fischer Titration
141
3
Karl Fischer Reagents and Reactions
142
1
Karl Fischer Titration Procedures
142
1
Method Development Issues in Karl Fischer Titration
143
1
Other Methods for Determining Water
144
1
Loss on Drying
144
1
Instrumental Methods
145
1
Miscellaneous Techniques
145
4
Differential Scanning Calorimetry and Thermal Analysis
145
1
References
146
3
Spectroscopy
149
36
Perlette Abuaf
Alvin J. Melveger
The Electromagnetic Spectrum
149
1
Wave-Particle Duality
149
2
Wave Parameters
150
1
Particle Parameters
151
1
Transitions and Energies
151
2
Ultraviolet/Visible Spectroscopy
153
3
Electron Type
153
1
Chromophores
153
2
Conjugation and Spectral Shifts
155
1
Infrared Spectroscopy
156
5
Group Frequencies
158
2
Fingerprinting
160
1
Beers Law and Quantitative Analysis
161
2
Transmittance
161
1
Effect of Concentration on Transmittance
161
1
Effect of Path Length on Transmittance
162
1
Instrumentation
163
14
UV/VIS Instrumentation
164
7
IR Instrumentation
171
6
Raman Spectroscopy
177
3
Raman Instrumentation
180
1
Near-IR (NIR) Spectroscopy
180
1
Other Optical and Spectroscopic Techniques
181
3
Polarimetry
181
1
Inductively Coupled Plasma (ICP) and Atomic Absorption Spectroscopy (AAS)
181
1
Mass Spectroscopy (MS)
182
1
Nuclear Magnetic Resonance (NMR) Spectroscopy
183
1
Summary
184
1
General References
184
1
Chromatographic Principles
185
32
James M. Miller
Definitions, Terms, and Symbols
185
13
Chromatography
185
2
The Chromatographic Process
187
2
Some Chromatographic Terms and Symbols
189
3
The Normal Distribution
192
1
Asymmetry and Tailing Factor
193
3
Plate Number
196
2
Comparison of GC and LC
198
1
Two Important Fundamentals
199
13
Thermodynamics of Chromatography
199
4
Kinetics
203
9
Some Additional Terms
212
3
Resolution
212
1
Retardation Factor
213
2
System Suitability
215
1
Summary
215
2
References
216
1
Gas Chromatography
217
38
James M. Miller
Harold M. McNair
Some Historical Notes
217
1
Advantages and Disadvantages
218
1
Classification of GC
219
1
Columns
220
6
Stationary Phases
220
1
Column Materials
221
1
Comparison of Column Types
222
1
Solid Supports
223
1
Solid Stationary Phases (GSC)
224
2
Other Instrument Components
226
15
Carrier Gas
227
2
Flow Control and Measurement
229
1
Sample Inlets and Sampling Devices
229
5
Detectors
234
7
Temperature Considerations
241
7
Temperature Zones
241
2
Programmed Temperature GC (PTGC)
243
5
Optimization and Method Development
248
1
Column Selection
248
1
Optimization According to Basic Principles
248
1
Some Special Topics
249
2
Gas Chromatography/Mass Spectrometry (GC/MS)
249
1
Derivatization
250
1
Headspace Sampling
250
1
USP
250
1
Applications
251
4
Analysis of Residual Solvents
251
1
References
252
3
Liquid Chromatography: Basic Overview
255
28
Lee N. Polite
Introduction
255
6
Importance of HPLC in the Pharmaceutical Industry
255
1
Column Versus Planar Liquid Chromatography
256
1
Low-Pressure Versus High-Pressure Liquid Chromatography
256
2
Advantages and Disadvantages of HPLC
258
1
Isocratic Versus Gradient Elution
258
3
Column Methods
261
7
Normal Phase
261
1
Reversed Phase
262
1
Ion-Exchange Chromatography
263
1
Ion Chromatography (IC)
264
1
Ion Pair Chromatography (IPC)
265
1
Size Exclusion Chromatography (SEC)
266
2
Planar Methods: TLC and PC
268
2
Quick and Dirty Procedures
268
1
Automation and Special Equipment
269
1
High-Performance Thin-Layer Chromatography (HPTLC)
269
1
Advantages and Disadvantages of TLC
269
1
USP
270
1
Instrumentation for HPLC
270
9
Pumps
270
2
Sample Introduction Devices
272
1
Tubing and Connectors
273
1
Detectors
274
3
Troubleshooting
277
2
Capillary Electrophoresis (CE)
279
4
CE Systems
280
1
References
281
2
HPLC Column Parameters
283
26
Richard Hartwick
Column Equivalency
284
1
Review of Chromatographic Parameters
285
2
Parameters Necessary for Equivalent Columns
287
8
Retentiveness and Selectivity
288
7
Peak Shape
295
1
Column Efficiency
295
7
Resolution
297
1
Reduced Plate Heights to Estimate Expected Column Efficiencies
297
5
Putting It All Together---Selecting an Equivalent Column
302
7
Choosing Equivalent Columns: An Example
303
4
References
307
2
Dissolution
309
22
Ross Kirchhoefer
Rudy Peeters
Introduction
309
2
History
310
1
Early Improvements in Dissolution Equipment
311
1
Dissolution Basics
311
4
Disintegration Tests
311
2
Elementary Theory
313
1
Practical Aspects
313
1
Dissolution Specifications
314
1
USP/NF Pharmacopeia General Chapter <711>
315
11
Apparatii
315
1
Parameters Affecting the Dissolution Test
315
7
Test Equipment
322
1
Stage Testing
322
1
Calibrators
323
1
Sampling
323
3
Measurement of the Pharmaceutical Active
326
2
Analyst Checklist
328
3
References
328
3
Analytical Method Development for Assay and Impurity Determination in Drug Substances and Drug Products
331
40
Jonathan B. Crowther
Paul Salomons
Cindi Callaghan
Background
331
1
Introduction
332
6
Specifications and Their Influence on Method Development
333
1
International Guidelines and Their Influence on Method Development
333
5
The Method Development Life Cycle---Overview
338
1
Planning
338
9
Review Company Policy on Method Development/Validation
338
2
Defining the Objectives/Requirements of the Method
340
1
Illustration of Method Requirements
341
3
Information Gathering
344
2
Resource Gathering: Resources/Instrumentation/Materials and Standards
346
1
Documentation: Development Plan
346
1
Method Development---General Considerations
347
4
Initial Method Development
347
1
Method Optimization
348
1
Method Prevalidation Evaluation
348
1
Robustness
349
1
System Suitability
350
1
Documentation
351
2
Method Development Report
351
2
Completing Method Development
353
1
Method Development---Experimental Considerations
353
8
Introduction
353
1
General Components of HPLC Method Development
353
6
Obtaining Sufficient Resolution---Considering Method Requirements
359
2
Validation Activities
361
2
Documentation---Protocol
362
1
Method Validation---Experimental
362
1
Documentation---Report
362
1
Analytical Method Transfer
363
1
Documentation---Protocol
363
1
Method Transfer---Experimental
364
1
Documentation---Transfer Report
364
1
Periodic Review
364
1
Reference Standards and Samples to Support Stability Indicating Method Development
365
3
Types of Standards
365
1
Handling of Standards
366
2
Summary
368
3
References
369
2
Some Principles of Quantitative Analysis
371
24
James M. Miller
Detector Classifications (Chromatographic)
372
3
Concentration Versus Mass Flow Rate
372
1
Bulk Property Versus Solute Property
372
2
Selective Versus Universal
374
1
Detector Characteristics
375
10
Noise
375
2
Time Constant
377
4
Cell Volume
381
1
Signal
381
4
Methods of Quantitative Analysis
385
7
Standards and Calibration
385
2
External Standard
387
1
Area Normalization
388
1
Area Normalization with Response Factors
388
1
Internal Standard Method
389
1
Standard Addition Method
390
1
Summary
391
1
Additional Topics
392
3
Trace Analysis
392
1
The High--Low Method for HPLC
392
1
References
392
3
Laboratory Data Systems
395
28
R. D. McDowall
Introduction
395
2
Data and Information Management
395
1
Purpose of Data Systems
396
1
Types of Data System
396
1
Laboratory Information Management Systems (LIMS)
397
4
A LIMS Has Two Targets
398
1
Benefits of a LIMS
399
1
Regulatory Issues
400
1
Chromatography Data Systems
401
2
Analog-to-Digital (A/D) Conversion
403
9
Rationale for A/D Conversion
403
1
Priciples of A/D Conversion
403
5
Peak Detection
408
4
CDS Workflow
412
8
Sequence of Data System Operation
412
5
Instrument Control
417
1
Interfacing CDS to Laboratory Information Management Systems
418
2
Concluding Remarks
420
3
References
420
3
Qualification of Laboratory Instrumentation, Validation, and Transfer of Analytical Methods
423
60
Jonathan B. Crowther
M. Ilias Jimidar
Nico Niemeijer
Paul Salomons
Introduction
423
1
Instrument Qualification
424
5
Instrumentation Life Cycle
425
1
Introduction---Qualification Versus Calibration
426
1
Prospective Versus Retrospective
426
3
Instrument Qualification Process---Assembly of the Qualification Team
429
1
The Qualification Protocol
429
1
IQ Protocol
430
5
Installation Qualification
430
2
Operational Qualification
432
1
Performance Qualification
432
1
Ongoing Monitoring
432
1
Final Qualification Report
433
2
Instrument Qualification Summary
435
1
Analytical Method Validation
435
6
Introduction to Method Validation
435
1
Determining the Characteristics of the Validation
436
1
Definitions
436
2
Method Validation Documentation
438
3
A Systematic Approach to Validation Experimentation
441
15
Determination of Method Specificity
441
2
Demonstration of Linearity and Range; Determination of Relative Response Factor
443
3
Determination of Detection and Quantitation Limit
446
1
Demonstration of Accuracy of the Method
446
1
Determination of Method Precision
447
1
Target Acceptance Criteria
447
4
Final Method---Minor Method Refinement
451
1
Validation Summary
451
2
Method Transfer
453
1
Transfer Documentation
454
1
Method Transfer Protocol
455
1
Method Transfer Experimental
456
1
Transfer Summary and Approval
456
1
Chapter Summary
456
3
References
457
2
APPENDIXES
I List of Symbols and Acronyms
459
8
II Glossary of Terms Used in ICH Documents
467
6
III Universal Tests, Dosage-Form-Specific Tests, and Acceptance Criteria
473
4
IV USP Chromatographic Phases
477
6
Index
483