Cambridge Healthtech Institute’s Tenth Annual 
Lyophilization and Emerging Drying Technologies
Formulation and Process Optimization, QbD, Process and Scale-Up Challenges
January 10-11, 2017 | Hilton San Diego Bayfront | San Diego, CA

The popular Tenth Annual Lyophilization and Emerging Drying Technologies conference covers latest trends and challenges in lyophilization and emerging drying technologies. This conference features in-depth case studies, new and unpublished data and discussions on developing scientifically sound formulation, process optimization for biologics and vaccines. It also presents cutting-edge research and case studies on freeze/thaw and formulation challenges, storage stability, particulates issues, QbD and PAT approaches and strategies for scale-up from R&D scale to full production level, and selection of container closure systems.

TUESDAY, JANUARY 10

1:00 pm Conference Registration

1:30 Refreshment Break in the Exhibit Hall with Poster Viewing

QbD, PAT, PROCESS SCALE-UP AND TECH TRANSFER

2:00 Chairperson’s Opening Remarks

Serguei Tchessalov, Ph.D., Associate Research Fellow, Bio Therapeutics R&D, Pfizer

Keynote Presentations

2:05 Resolving Scale-Up Problems in Freeze Drying: Differences in Dry Layer Resistance and in Effective Vial Heat Transfer Coefficients

Michael Pikal, Ph.D., Distinguished Endowed Chair in Pharmaceutical Technology & Professor, Department of Pharmaceutics, University of Connecticut

The two major scale-up problems associated with primary drying originate because of differences in ice nucleation temperature, thereby causing differences in mass transfer through the dry layer, and in vial heat transfer coefficients, causing differences in heat input. Here we present theoretical results and both laboratory and manufacturing data that address these differences and also outline procedures by which one can make adjustments to laboratory results for application to production.

2:45 An Industry Prospective on Application of Modeling to Lyophilization Process Scale-Up and Transfer

Serguei Tchessalov, Ph.D., Associate Research Fellow, Bio Therapeutics R&D, Pfizer

For many years, lyophilization process transfer and scale-up was a trial-and-error exercise. This talk will focus on an assessment of the current state of lyophilization process modeling and its role in efficient cycle transfer and scale-up. The assessment is based on combined experience of a few pharmaceutical companies that are collaborating on developing a harmonized approach to scale-up and tech transfer. The talk will also share the industry outlook on future strategies towards efficient and cost-effective implementation of commercial processes.

3:15 New Methods and Simple Approaches for Cycle Optimization & Transfer

T.N. Thompson, President, Millrock Technology, Inc.

The use of the unique product temperature control system, AutoDry, and its importance for cycle optimization through maximum heat input will be discussed. The use of LyoPAT II and the direct measurement of Kv for cycle transfer is illustrated along with LyoSim, a freeze dryer simulator.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 New Case Studies and Strategies for Manufacturing, Scale-Up and Tech Transfer

Alexander P. Herbert, Senior Process Engineer, Process Engineering and Pilot Plant, West-Ward Pharmaceuticals

Scaling and transfer is the most challenging step of process development, and success is firmly reliant both on strong experimental design principles and thorough understanding of equipment capabilities. This presentation will cover many important facets of scaling and transfer of lyophilization processes through case studies of two peptide product formulations.

5:00 Innovative Approaches for Lyophilization Process, Equipment and Drug Product Characterization

Ahmad M. Abdul-Fattah, Ph.D., Senior Scientist, Lyophilization Unit, Coriolis Pharma

Heat flux sensors are non-invasive alternatives to thermocouples and represent a promising PAT tool for lyophilization process monitoring, characterization and process control. We will shed light on some applications of this new tool for process characterization during and primary drying. On a different note, we will present some applications of headspace moisture analysis as a non-invasive high-throughput method for product, process and equipment characterization.

5:30 Close of Day

WEDNESDAY, JANUARY 11

8:00 am Conference Registration and Morning Coffee

ROLE OF WATER AND ICE

8:30 Chairperson’s Remarks

Bradley D. Anderson, Ph.D., Professor, Pharmaceutical Sciences, University of Kentucky

8:35 Role of Water in Chemical Instability of Freeze-Dried Proteins: Plasticization vs. Water Catalysis

Evgenyi Shalaev, Ph.D., Research Investigator, Pharmaceutical Development, Allergan

Water is a major factor which influences stability of lyophilized proteins. In this presentation, water’s role in chemical instability of freeze-dried formulations is reconsidered, based on the analysis of specific chemical processes, i.e., amide hydrolysis and deamidation reactions. Water catalysis probably plays a major role in these reactions, whereas contribution from plasticization and molecular mobility enhancement is minor.

9:05 Mobility and Water Dependent Chemical Reaction Pathways in Lyophilized Formulations of Peptides and Proteins

Bradley D. Anderson, Ph.D., Professor, Pharmaceutical Sciences, University of Kentucky

This presentation focuses on chemical reactions of lyophilized peptides and proteins at particular “hot spots” (e.g., asparagine and cysteine residues). Molecular mobility/heterogeneous relaxation and the distribution of the drug, water, and excipients play a critical role in amorphous solid-state reactions. The multi-step nature of most peptide/protein reactions requires that one identify the rate-determining step and reactive intermediates in order to predict the rate of degradation and reaction products. Shifts in the dominant pathway often occur in response to differences in water content, reactant mobility, and proximity of reactant molecules.

9:35 Influence of Process Conditions on Spatial Distribution of Individual Vial Heat Transfer Coefficients

Lindsay Wegiel, Ph.D., Research Scientist I, Pharmaceutical Development, Baxter

Kv is typically determined as an average value for a whole shelf of vials. This study has determined that there is a large range of Kv values depending on the vials placement on the shelf. The spatial distribution of Kv was influenced by the process conditions (chamber pressure and shelf temperature). In some cases the range of Kv values was minimal; however, other instances led to a wide range of Kv values.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:50 Optimization of a Low-Volume Resuscitation Fluid Formulation to Treat Hemorrhagic Shock

Seema Thakral, Ph.D., Research Associate, Department of Pharmaceutics, University of Minnesota

A combination of melatonin (M) and D-ß-hydroxybutyrate (BHB) increases survival in animal hemorrhagic shock models. To achieve adequate melatonin solubility, the current BHB/M formulation contains 20% v/v dimethylsulfoxide (DMSO). Our objectives were to: 1) formulate a novel BHB/M, solid dosage form which can be readily and rapidly reconstituted into an aqueous solution, and 2) evaluate the efficacy of the formulation in a rat hemorrhagic shock model. Lyophilized BHB/M formulation showed adequate drug solubility and the cycle was optimized to generate an elegant, readily reconstitutable formulation.

MODELS AND TOOLS

11:20 Benchtop Methods for Predicting Stability of Freeze-Dried Proteins

Marcus T. Cicerone, Ph.D., Biomaterials Group, National Institute of Standards and Technology

The basic physics governing stabilization in the dry state is only now beginning to be understood, but reliable and accessible methods for measuring these processes have not been developed. As a consequence, engineering of the dried sugar formulations is currently based on a combination of weakly predictive metrics and long-term stabilization studies, leading to a situation in which there is much time and effort expended in finding optimal formulations. I will present bench-top methods for measuring the picosecond and nanosecond timescale dynamic processes that facilitate degradation of proteins in solid form.

11:50 Modeling the Secondary Drying Stage of Freeze Drying: Development and Validation of an Excel-Based Model

Ekneet Sahni, Ph.D., Senior Process Development Engineer, Manufacturing Science and Technology (MSAT), Pfizer

The purpose of this work is to develop and validate a simplified Excel-based secondary drying model that could aid in optimization of lyophilization processes minimizing the cycle development time. Comparisons were made between the Excel calculations and the experiments conducted using sucrose at different processing conditions. Agreement was satisfactory, being quantitative in most cases. Future studies will involve model validation for representative amorphous as well as partial-crystalline protein based formulations.

12:20 Lyophilizer Sublimation and Heat Transfer Modelling – Building Comparability and Scalability Models for Bioproducts – An Industrial Case Study

Timothy R. McCoy, MSc, Principal Scientist, Technical Development, Sanofi Ireland

12:50 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

CRITICAL CONSIDERATIONS IN PRODUCT DEVELOPMENT: FORMULATION, STABILITY, PARTICLES AND PACKAGING

2:00 Chairperson’s Remarks

Wendy Saffell-Clemmer, MS, Director, Research, Pharmaceutical Development, Baxter Healthcare

2:05 Selection of Pre-Filled Syringe for Biologic Products on Particulate Matter and Product Stability – A Case Study

Wendy Saffell-Clemmer, MS, Director, Research, Pharmaceutical Development, Baxter Healthcare

Pre-filled syringes provide significant advantages to the clinician and the patient. However, the pre-filled syringe and syringe filling process can have a significant impact on particulate formation and product stability. Methodical laboratory studies on the formulation are needed to understand potential causes of particle formation. A case study describing development of a liquid monoclonal antibody pre-filled syringe product will be presented along with a discussion of manufacturing scale-up challenges.

2:35 Developing a Multi-Pronged Approach to the Identification of PS20 Degradation Mechanism

Anthony Tomlinson, Senior Research Associate, Late Stage Pharmaceutical Development, Genentech

Polysorbates are commonly used non-ionic surfactants in protein pharmaceuticals. In recent years, there has been increasing concern in the degradation of these materials on long-term stability and the subsequent increase of insoluble degradation products. In this talk, we will discuss the detection of PS20 degradation products and the identification of the mechanism of degradation for root cause analysis.

3:05 Subvisible Particles: Rapid and High-Throughput Tools for Prediction, Detection and Characterization of Subvisible Particles and Other Aggregates

Andrea Hawe, Ph.D., CSO, Coriolis Pharma

Aggregates and subvisible particles (SVP) are considered cQA for biologics, and it is crucial to include a comprehensive characterization early during drug product development. Especially, for early development a reduction of required time, material and resources is essential. Within the talk, an overview of methods and strategies for SVP and aggregate analysis is given, with special focus on minimization of material requirements, increase in throughput and possibilities for prediction of stability.

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:30 Prediction of Antibody Stability in Lyophilized Solids by Hydrogen Deuterium Exchange with Mass Spectrometric Analysis (HX-MS)

Kathleen Abadie, Engineer I, Pharmaceutical Development, Genentech

We explore HX-MS to study protein structure in lyophilized solids for deeper understanding of solid state stability and to save time and resources in pharmaceutical development. HX probes structure by measuring the frequency of stabilizing amide H-bonds. Indeed, we show that reduced stability as indicated by increased deuterium uptake versus time correlates with increased aggregation propensity. Stability effects of lyoprotectant concentration and processing conditions are assessed by HX-MS.

View Speaker Interview

5:00 Scaled Down Containers for Protein Stability Studies

Eric Meinke, Ph.D., Senior Scientist, AstraZeneca Supply Biologics

Real-time, real-condition stability study is essential to establish the expiry of biological therapeutics. For drug substances, stability study is typically performed in small scale containers that mimic the actual storage container/condition at scale. A case study will be presented to highlight the criticality of understanding and controlling of the scaled down container for stability studies.

6:20-7:20 Reception in the Exhibit Hall with Poster Viewing

7:20 Close of Conference