Specification of Drug Substances and Products

Specification of Drug Substances and Products: Development and Validation of Analytical Methods, Third Edition contains chapters discussing the unique requirements for the universal critical quality attributes, as well as the specific tests required to characterize and control different types of products, ranging in complexity from small molecules in immediate release oral dosage forms to complex products such as drug-antibody conjugates and mRNA-based products. This substantially expanded revision of the second edition will serve as practical comprehensive reference for scientists, managers, educators, and consultants involved in the development and regulation of pharmaceutical products.

Cover image
Title page
Table of Contents
Copyright
Contributors
About the editors
Section I. Introduction
Chapter 1. Introduction
1.1. Historical perspective
1.2. Specifications: General principles
1.3. Analytical methods
1.4. Validation of analytical methods and the reporting of analytical results
1.5. Conclusions
Section II. Regulatory considerations and statistical approaches
Chapter 2. Principles for setting specifications and shelf lives
2.1. Introduction
2.2. Regulatory requirements and guidelines
2.3. Specification setting process
2.4. Elements to include in specifications
2.5. Scientific considerations in setting acceptance criteria
2.6. Statistical considerations for setting acceptable limits
2.7. Evaluation of stability data and determination of shelf life
2.8. Conclusions
Chapter 3. Stability studies: General regulatory considerations and regional differences
3.1. Introduction
3.2. Global stability programs to support drug development
3.3. ICH stability program
3.4. WHO stability guideline
3.5. ASEAN stability guideline
3.6. ANVISA stability guideline
3.7. Vaccine stability program
3.8. Drug-device combination product stability
3.9. Conclusions
Chapter 4. Kinetics and mechanisms of drug degradation
4.1. Introduction
4.2. General principles
4.3. Mechanisms of drug degradation
4.4. Conclusions
Chapter 5. Analytical procedure life-cycle management
5.1. Introduction
5.2. Analytical method development and method performance control
5.3. Modality, technology, and development phase-specific considerations
5.4. Conclusions
Chapter 6. Process analytical technology
6.1. Introduction
6.2. Drivers behind the development and implementation of process analytical technology
6.3. Quantifiable benefits of process analytical technology
6.4. Additional considerations of process analytical technology
6.5. Conclusions and future directions
Chapter 7. Pharmacopeial methods and tests
7.1. Introduction
7.2. Legal recognition
7.3. Requirements for inclusion in a pharmacopeia
7.4. Revision process
7.5. Input from regulatory authorities
7.6. Pharmacopeial harmonization
7.7. Content of monographs
7.8. Compendial reference standards
7.9. Conclusions
Chapter 8. Development of United States Pharmacopeia-National Formulary (USP–NF) Monographs and General Chapters
8.1. Introduction
8.2. Structure of the USP-NF compendium
8.3. The standard setting process for the USP-NF
8.4. Revision process for Monographs and General Chapters
8.5. The appeals process
8.6. Harmonization of Monographs and General Chapters
8.7. New dosage forms of existing drugs
8.8. Analytical method management
8.9. Further method development to implement a procedure
8.10. Conclusions
Chapter 9. The distinctiveness of the British Pharmacopoeia and its relationship to other Pharmacopeia
9.1. The British Pharmacopoeia
9.2. Content, organizational structure and management
9.3. Harmonization
9.4. Tests and methods: An academic user's perspective
9.5. Reference standards
9.6. Recent developments
9.7. Conclusions
Chapter 10. Specifications and analytical procedures in registration applications
10.1. Introduction
10.2. Guidelines relevant for specifications and analytical methods in registration applications
10.3. Preparation of a core submission dossier for registration applications
10.4. Interactions with regulatory authorities
10.5. Regulatory perspective of GMP aspects and inspections
10.6. Post-approval activities
10.7. Conclusions
Chapter 11. Specifications and analytical procedures in clinical trial applications
11.1. Introduction
11.2. Principles for the CMC part of a CTA/IND
11.3. Guidance relevant for the CMC content in CTA/IND submissions
11.4. Preparation of a quality dossier for clinical trial applications
11.5. CTA/IND submission, review, approval and amendments
11.6. Interactions with regulatory authorities
11.7. Regulatory perspective of GMP aspects and inspections
11.8. Conclusions
Section III. Critical quality attributes
Chapter 12. Description and identification
12.1. Introduction
12.2. Description
12.3. Drug substance identification testing
12.4. Drug product identification
12.5. Conclusions
Chapter 13. Assay and impurities: Specifications of new chemical entities (“small molecules”)
13.1. Introduction
13.2. Analytical methodology
13.3. Calculations
13.4. Analysis of samples
13.5. Specification of assay and impurities
13.6. Other applications of assay methods
13.7. Conclusions
Appendix A.13. Rules of rounding, significant figures and use of spreadsheets
Chapter 14. Assay and impurities: Method development as part of analytical life-cycle management
14.1. Introduction
14.2. Rational design of analytical methods
14.3. Techniques and mode selection based on physicochemical properties
14.4. Maximizing orthogonality using column screening and mobile phase screening
14.5. Systematic and efficient column and mobile phase screening
14.6. Method optimization and robustness using simulation software
14.7. Enhanced selectivity, peak capacity, orthogonal methods and two-dimensional chromatography
14.8. Cases studies: Examples of systematic method development
14.9. Conclusions
Chapter 15. Assay and impurities: Method validation
15.1. Introduction
15.2. Validation of methods for assay, impurities, and related procedures
15.3. Conclusions
Chapter 16. Mutagenic impurities
16.1. Introduction
16.2. Assessment and control as a function of the life-cycle
16.3. Developing control strategies
16.4. Impurities to be considered for mutagenic risk assessment (MRA)
16.5. Analytical challenges and strategies
16.6. Case study 1 – galunisertib
16.7. Case study 2 – pazopanib hydrochloride
16.8. Case study 3 – N-nitrosamines in sartans
16.9. Conclusions
Chapter 17. Residual solvents
17.1. Introduction
17.2. Residual solvent classes
17.3. Supplier management
17.4. Risk assessment
17.5. Specifications and acceptance criteria
17.6. Analytical methods
17.7. Analytical methods validation
17.8. Conclusions
Chapter 18. Elemental and inorganic impurities
18.1. Scope
18.2. Introduction
18.3. Compliance requirements
18.4. Elemental impurity classification
18.5. Permitted daily exposure limits
18.6. Compliance options
18.7. Preparing a risk assessment
18.8. Analytical techniques
18.9. Method development
18.10. Method validation
18.11. Other compendial methods for inorganic impurities
18.12. Life-cycle management
18.13. Conclusions
Chapter 19. Extractables and leachables
19.1. Introduction
19.2. Materials risk assessment
19.3. ISO 10993-18 – medical device
19.4. Extractable analysis
19.5. Leachables study
19.6. Leachables study design
19.7. Impact of leachables in the drug product above the AET
19.8. Conclusions
Chapter 20. Microbiology methods
20.1. Introduction
20.2. General microbiology practices
20.3. Microbial testing for non-sterile products
20.4. Testing for sterile products
20.5. Particulate matter in injection products
20.6. Commonly used USP microbiology informational chapters
20.7. Alternative microbiological methods
20.8. Conclusion
Chapter 21. Solid-state characterization methods: An overview
21.1. Introduction
21.2. Relevance of solid-state characterization
21.3. ICH guidelines and potentially controlled solid-state parameters
21.4. Timing of solid-state characterization development
21.5. Methods overview
21.6. Method selection for crystalline/amorphous quantification
21.7. Conclusions
Chapter 22. Solid-state characterization – Method development and validation
22.1. Introduction
22.2. Method validation
22.3. Sample preparation
22.4. Sample selection
22.5. Data normalization
22.6. Feasibility testing
22.7. Identification tests
22.8. Limit tests
22.9. Quantitative methods
22.10. System suitability and goodness-of-fit
22.11. Conclusions
Chapter 23. Chiral methods
23.1. Introduction
23.2. Implementation of health authority guidelines to chiral drug development
23.3. Chiral LC
23.4. Other chiral separation methods
23.5. Non-separation techniques
23.6. Chiral method validation
23.7. Conclusions
Chapter 24. Water determination
24.1. Introduction
24.2. Loss on drying (LOD)
24.3. Karl Fischer Titration (KFT)
24.4. Gas chromatographic methods
24.5. Near-infrared spectroscopy (NIRS)
24.6. Dynamic vapor sorption
24.7. Sampling and sample preparation
24.8. Conclusions
Section IV. Dosage forms and product types
Chapter 25. Orally administered dosage forms
25.1. Introduction
25.2. Universal test methods
25.3. Specific test methods
25.4. Conclusions
Chapter 26. Drug release: Topical products
26.1. Introduction
26.2. In vitro release test
26.3. Method development
26.4. IVRT method validation
26.5. Common sources of variability in IVRT methods
26.6. Regulatory guidelines
26.7. Conclusions
Chapter 27. Transdermal products
27.1. Introduction
27.2. Product quality document relationships to test method development
27.3. Drug substance
27.4. Adhesive raw material
27.5. Excipient and component raw materials
27.6. Drug product
27.7. Chemical methods
27.8. Functional performance methods
27.9. Physical property methods
27.10. Microbiological methods
27.11. In-process controls
27.12. Extractables and leachables
27.13. Laboratory support operations
27.14. Conclusions
Chapter 28. Inhalation products
28.1. Introduction
28.2. Drug substance for use in inhalation
28.3. Drug products for inhalation
28.4. Conclusions
Chapter 29. Ophthalmic products
29.1. Introduction
29.2. Specifications and methods for ophthalmic products
29.3. Universal specifications and test methods
29.4. Specific test methods and specifications
29.5. Intraocular ophthalmic products
29.6. Conclusions
Chapter 30. General analytical considerations for parenteral products
30.1. Introduction
30.2. Quality target product profile for parenteral products
30.3. Critical quality attributes for parenteral products
30.4. Quality specifications for parenteral products
30.5. Critical aspects related to registration of parenteral drug products
Chapter 31. Specification of biotechnology products including cell and gene therapy
31.1. Introduction
31.2. Regulatory considerations
31.3. Specification of drug substance and drug product
31.4. Specification of drug substance
31.5. Specification of drug product
31.6. Specification of cell and gene therapy (CGT)
31.7. Justification of specification
31.8. Challenges and issues in specification development
31.9. Conclusions
Chapter 32. Biotechnology products: Validation of analytical methods
32.1. Introduction
32.2. Method design and the analytical target profile
32.3. Method validation
32.4. Compendial method verification
32.5. Continuous method usage
32.6. Prior knowledge
32.7. Guidelines
32.8. Conclusions
Chapter 33. Biosimilars
33.1. Introduction
33.2. Analytical method development
33.3. Analytical methods: demonstration of fit-for-purpose and validation
33.4. Analytical similarity
33.5. Reference materials
33.6. Pharmacopeial monographs for biosimilars
33.7. Specification of biosimilars
33.8. Conclusions
Chapter 34. Antibody-drug conjugates
34.1. Introduction
34.2. Structure of an ADC
34.3. Overall control strategy for ADC drugs
34.4. Critical aspects for the characterization of ADCs
Chapter 35. Oligonucleotides
35.1. Introduction
35.2. Impurities
35.3. Analytical methods
35.4. Conclusions
Chapter 36. Specifications for vaccines
36.1. Overview of different vaccine modalities
36.2. General recommendations and justifications for vaccine specifications
36.3. Reflections on clinical relevance for vaccine specifications
36.4. Release and shelf-life specifications
36.5. Illustrative examples of different vaccine modalities, including COVID learnings
36.6. Challenges and opportunities for global regulatory harmonization of specifications
Chapter 37. Nanoparticle suspension dosage forms by nanomilling
37.1. Introduction
37.2. Universal test methods
37.3. Specific test methods
37.4. Conclusions
Chapter 38. Development of connected drug delivery systems
38.1. Introduction
38.2. Development of connected drug delivery systems
38.3. Deliverables
38.4. Design verification
38.5. Design validation
38.6. Development of mechanical parts
38.7. Development of embedded or stand-alone software
38.8. Conclusions
Section V. Biological fluids
Chapter 39. Bioanalysis of biological matrix samples using liquid chromatography-tandem mass spectrometry detection
39.1. Introduction
39.2. Technologies for the bioanalysis of biological matrix samples
39.3. Validation of LC-MS bioanalytical methods
39.4. Bioanalytical methods for proteins
39.5. Conclusion
Chapter 40. Bioanalysis of oligonucleotides
40.1. Introduction
40.2. Overview of bioanalytical methods for oligonucleotides
40.3. LCMS assays for the bioanalysis of oligonucleotides
40.4. Ligand binding assays for the bioanalysis of oligonucleotides
40.5. qPCR assays for the bioanalysis of oligonucleotides
40.6. Conclusions
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Specification of Drug Substances and Products

Development and Validation of Analytical Methods

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Christopher M. Riley

K. Lien Nguyen