Freeze-drying of Pharmaceuticals and Biopharmaceuticals

1: Historical Background;

1.1: Drying as a preservation method;

1.2: The advent of industrial freeze-drying;

1.3: Elements of stability;

1.4: Why Freeze-Dry?;

1.5: Stability - the downside;

2: The Process Sequence in Summary;

2.1: Equipment;

2.2: The drying process - coupled heat and mass transfer;

2.3: How dry is "Dry"?;

2.4: Why not freeze-dry?;

3: Essential Product and Process Parameters;

3.1: General considerations;

3.2: Formulation parameters;

3.3: Process parameters;

3.4: The multidisciplinary nature of freeze-drying;

3.5: Conclusions;

4: Essential Physics of Low Temperature and Freezing;

4.1: Chill versus freezing - undercooling;

4.2: Deep chill - undercooled water;

4.3: Physical properties of undercooled water;

4.4: Ice - nucleation in undercooled water;

4.5: Ice - its crystallisation and crystal habits;

4.6: Nucleation and crystallisation of ice and solutes in aqueous solutions;

4.7: Polymorphic transitions, hydrates and transient hydrates;

4.8: Vitrification as avoidance of crystallisation;

4.9: Freezing in complex biological substrates;

5: Essential Chemistry and Biochemistry associated with low temperature and freezing;

5.1: Physicochemical properties of water-based systems under conditions of deep chill;

5.2: Cold inactivation of proteins;

5.3: Changing phase relationships during freezing;

5.4: Eutectic crystallisation of pH buffer components;

5.5: Effects of freeze concentration on reaction kinetics;

5.6: Complex ternary and multicomponent phase behaviour;

5.7: Supersaturation and vitrification: importance of the state diagram;

5.8: Aqueous glasses as solid solutions;

6: Physical properties of crystalline and amorphous solids;

6.1: Crystalline and amorphous solids - a comparison;

6.2: Non-equilibrium processes in amorphous solids;

6.3: Slow relaxation during cooling and heating;

6.4: The Glass Transition - a summary;

6.5: Amorphous states and freezing behaviour;

6.6: Materials science of the glass transition - its relevance to freeze-drying;

7: Excipients: their role in rational formulation design;

7.1: Definitions and classifications;

7.2: Attributes and requirements;

7.3: Estimation of Tg of complex mixtures;

7.4: Effects of excipients on product attributes;

7.5: Implications for freeze-drying;

7.6: Devitrification of excipients in dried amorphous preparations;

7.7: Pharmaceutical glasses - formulation aspects;

7.8: Constraints;

7.9: Operational degrees of freedom;

8: Primary Drying - the Sublimation of Ice;

8.1: Principles of coupled heat and mass transfer;

8.2: The model;

8.3: Heat transfer mechanisms;

8.4: Influences of formulation and freezing procedure on ice sublimation;

8.5: The interplay of pressure, temperature and time;

8.6: Adjustable parameters: Formulation, concentration and fill depth;

8.7: Ideal conditions;

8.8: Accelerated freeze-drying;

8.9: Monitoring ice sublimation;

8.10: Summary;

9: Secondary Drying;

9.1: Unfrozen (residual) water;

9.2: Removal of unfrozen water by diffusion;

9.3: Effects of pressure;

9.4: Effect of Water Content;

9.5: Effects of fill depth and cake morphology;

9.6: Effect of Temperature;

9.7: Softening and collapse;

9.8: Operational drying protocols - temperature ramping and stepwise heating;

10: Some Practical Aspects - Economics and Engineering;

10.1: Scale up and ICH manufacture;

10.2: Economics;

10.3: Vial closure;

packaging;

10.4: Process monitoring and control;

10.5: Stability issues;

11: The Dried Product;

11.1: Physical state: crystalline or amorphous?;

11.2: Essential materials science of crystalline and amorphous products;

11.3: Essentials of thermoanalytical techniques;

11.4: Fragility and its estimation;

11.5: Monitoring physical and chemical stability;

11.6: Estimation of useful shelf life;

11.7: Dynamics in supersaturated solutions;

11.8: Residual water and its estimation;

11.9: Residual water: its influence on stability;

11.10: Unresolved issues;

11.11: Reconstitution at point of use;

12: Case Histories;

12.1: Introduction;

12.2: Choice of formulation;

12.3: Process cycle optimisation;

12.4: Concurrent product and process refinement;

12.5: Inadvertent failures - "unexpected problems";

12.6: Unfamiliarity with freeze-drying parameters;

12.7: In situ water release during storage;

12.8: Summary and conclusions;

13: Beyond Freeze-drying;

13.1: Alternative water removal technologies;

13.2: Evaporative drying: principles and practice;

13.3: Evaporative drying: the current state;

13.4: Comparisons with freeze-drying;

14: Acknowledgements;

15: Bibliography