6th Annual Lyophilization and Emerging Drying …

1 2013 6th Annual Lyophilization and Emerging Drying Technologies Conference Review Pep Talk 2013 Protein Science Week, Renaissance Hotel & Palm Springs Convention Centre in Palm Springs, California USA 21st-25th of January, 2013. E. Ekenlebie, A. Ingham Aston University Document release date: 05/04/13 2 Edmond Ekenlebie Contents 1 Summary .. 3 2 Buzz Sessions .. 4 BuzZ Session A: Improving Lyophilization by Annealing .. 4 BuzZ Session B: QbD in Freeze Drying and Design of the Freezing Process .. 5 3 Presentations from Main Conference Days 1 and 2 .. 5 Advances in Controlled Nucleation.

2 5 Lyophilization Cycle Development: Navigating the Path to a Biological Animal Health Vaccine Product .. 7 Beyond Controlled Nucleation .. 8 Risk Mitigation in Lyophilization Process Development and Tech Transfer .. 8 Formulation Strategies for Successful Spray Drying and Case Studies .. 9 Phase behaviour of Excipients in Lyophilized Formulations: Potential Implications on Product Performance .. 10 Mannitol Crystallinity and Stability of IgG in Lyophilized Formulations .. 11 Scale-Up of Controlled Nucleation to a Production Environment .. 12 Challenges and Considerations for Developing Lyophilized Biopharmaceuticals .. 12 New Process Technologies for Fast, Continuous Freeze Drying .. 14 Spray-Dried Biopharmaceutical Powders for Drug Substance Bulk Storage Application.

3 15 Lyophilization of Saccharide and Salt Containing Systems in Bottles: Collapse, Crystallization, and Implications .. 16 Controlled Nucleation: The Impact of Nucleation Method and Freezing Temperature on the Process and Properties of Freeze Dried Sample .. 17 5 18 Submitted Poster Abstract .. 18 Poster Award .. 19 3 Edmond Ekenlebie 1 Summary A report capturing personal notes from the 6th Annual Lyophilization and Emerging Drying Technologies Conference held from 22nd-24th January, 2013. This conferences was part of the Pep Talk 2013 Protein Science Week held at the Renaissance Hotel & Palm Springs Convention Centre in Palm Springs, California USA from 21st-25th of January, 2013.

4 4 Edmond Ekenlebie 2 Buzz Sessions Buzz sessions were forty five minutes round table discussions held on Tuesday, January 22nd, 2013 prior to the main conference event. Attendees were free to participate in any of the 42 discussion sets. The timing of these sessions meant one could only attend 2 of 4 closely related to lyophilisation. BuzZ Session A: Improving Lyophilization by Annealing This session was chaired by Charlie (Xiaolin) Tang, , Associate Director, Formulation Development, Regeneron Pharmaceuticals. Issues discussed included reducing Drying time, improving cake structure, annealing in an amorphous system and maximizing crystallinity using an optimal annealing step.

5 Annealing is performed between the Tg and Teu to encourage full crystallisation. Crystallinity can be measured using Differential scanning calorimetry (DSC) or X-ray Powder diffractometry (XRD) insitu. The use of DSC can be challenging and is easier investigating changes in glass transition (Tg) of a pure compound by measuring heat flow over time. Chair admitted his attempts via this route had not been encouraging. Benefits of annealing include a resulting increase in sublimation rate and decrease in primary Drying time. Lower product temperatures can be attained because of lower product resistance. It causes crystallisation of bulking agent at the freezing stage instead of during primary Drying . This prevents the vial breakage phenomenon as seen in mannitol.

6 Mannitol and glycine containing formulations are commonly annealed. Thicker product walls may result in pure amorphous systems when annealed. Annealing can also be performed on dry powders. The approach is to anneal a pure amorphous system below the Tg. This causes the redistribution of water. However, water redistributed homogenously is optimal when compared to water clusters which have less interaction with the API (increase stability). Annealing reduces free volume in a formulation. The higher the free volume, the lesser the stability due to increased molecular mobility. 5 Edmond Ekenlebie BuzZ Session B: QbD in Freeze Drying and Design of the Freezing Process Received apologies for chairman's absence.

7 Discussions were lead by Sajal Patel of Medimmune with input from all on various aspects of the subject area. Sajal stressed on a need for formulators to know the critical parameters of materials for cycle development. Process validation was discussed briefly. There was no one defined practice across the various companies represented. However it was common to design high and low energy demand cycles (for example 2 large cycles and 4 cycles at laboratory scale) as well as demonstrating with data that transfer to laboratory scale indeed worked. Using a typical influenza platform as an example, only lyophilisation robustness is of interest initially. Design space is looked into after phase 2.

8 Phase 1 and 2 were more about pace without wasting time. Smart lyo technology received praise across the table. Shelf mapping is a common requirement in industry usually every 2 years. There are differences in performance between brand new and aging dryers requiring periodic assessment. Yearly comparison of same cycle from a dryer may show slight differences. Historical data of production freeze dryers is important. Modifications may include fluid and condenser changes. Ramp rate and aggressive cycles are typical areas of caution. Knowledge of final dryer units, geometry and product limits are necessary. 3 Presentations from Main Conference Days 1 and 2 Advances in Controlled Nucleation Michael Pikal, , Pfizer Distinguished Endowed Chair in Pharmaceutical Technology & Professor of Pharmaceutics, University of Connecticut Addressed the absence of proper control of the nucleation during freezing as compared to other stages in freeze Drying which are directly controllable.

9 6 Edmond Ekenlebie Surface area of the cake is dictated by the surface area of the ice which in turn causes intra and inter batch variation as a result of interaction between protein and ice. Although it may not apply to all systems this explains the observed variations in aggregation across batches. Bias is commonly seen in thermocouple and non thermo coupled vials with collapse predominant in the latter. Non thermo coupled vials experience about 10 of supercooling resulting in smaller ice crystals and about 10% longer Drying time. Laboratory and clean room data showed similarities in nucleation temperature. Small temperature variations are seen in nucleation temperature of BSA-20% sucrose and 5% dextran systems.

10 Dr Pikal emphasised supercooling was a big challenge in manufacturing and went on to explain the current available techniques for controlled nucleation. Ice fog Technique by IMA LIFE: Super cools product without freezing causing the chamber to be humid. Pressure is reduced with introduction of nitrogen which forms ice when it hits the humid air and pushes the ice into the vials to trigger crystal growth. Freeze Booster by Millrock: Also an Ice fog technique. It can be cheap to retrofit to existing dryers since it does not require a high pressure capability. Control Lyo by Praxair:Technique uses a depressurisation mechanism. Drying chamber is pressurised with an inert gas and shelves are cooled to desired nucleation temperature.