Summary: In 2019, the U.S. FDA approved a total of 47 lyophilized drug applications submitted by 37 companies. Information on generic drugs was compiled from FDA’s Orange Book database, not including drugs listed with any of the following conditions: discontinued, solution dosage form, routes of inhalation, oral, spinal, and intrathecal administration. Overall, 87% (41) of the FDA approved lyophilized drugs are generic products, followed by 9% (4) new drug applications (NDA) and 4% (2) of new biologics. By indication, oncology comprised the largest category of FDA approved lyophilized drugs at 47%, followed by infectious disease (34%), surgical use (7%), and others (metabolic, virology, neurology, diagnostics use, digestive, and rare diseases) at 2% each in 2019. Additionally, in 2019 EMA approved 4 lyophilized drugs for oncology (2), infectious (1), and metabolic (1) diseases. The following tables and infographics are constructed from data collected from the European Medicine Agency website, U.S. Food and Drug Administration websites and databases, and DailyMed website, all accessible online.
LyoPRONTO: An Open Source Lyophilization Process Optimization Tool
This work presents a new user-friendly lyophilization simulation and process optimization tool, freely available under the name LyoPRONTO. It is a new lyophilization simulation and process optimization tool. It includes freezing, primary drying modeling and optimization modules as well as the design space generator (Figure 1(b)). It can be used to model the lyophilization process and create more efficient cycles. Moreover, the tool is capable of determining the vial heat transfer parameters and product resistance characteristics, thus reducing the number of experiments.
The 0D lumped capacitance modeling approach is used in a freezing calculator to predict the product temperature variation with time and results in reasonably good agreement with experimental measurements. The primary drying calculator is based on 1D heat and mass transfer analysis (Figure 1(a)) in a vial and deviation from the experimental data is within 3% (Figure 1(d)).
The optimization tool enables acceleration of the primary drying cycle by 62% for 5% Mannitol (Figure 1(c)) and by 50% for sucrose solutions in comparison to traditional cycles. Thus, coupling with controllers and accurate sensors will allow creating self-driving lyophilizers.
For more information and to launch LyoPRONTO, visit https://sites.google.com/view/rgdart/Research/lyopronto-lyophilization-processoptimization-tool
Fundamentals of Freeze Drying I: Introduction and Process Overview (Advantages and limitations of freeze drying, Product quality attributes, Process overview: freezing, primary drying, secondary drying) https://pharmahub.org/resources/745
Fundamentals of Freeze Drying II: The Freezing Process (Supercooling and ice nucleation, Characterization of freezing behavior, Establishment of upper product temperature limit during primary drying) https://pharmahub.org/resources/746
Fundamentals of Freeze Drying III: Primary and Secondary Drying (Primary Drying: heat transfer considerations, measurement of the vial heat transfer coefficient, mass transfer considerations, measurement of the resistance of the dried product layer and Secondary Drying: critical process variables during secondary drying, how dry is "dry enough") https://pharmahub.org/resources/747
Fundamentals of Freeze Drying IV: Process Monitoring https://pharmahub.org/resources/748
Fundamentals of Freeze Drying V: Formulation Considerations https://pharmahub.org/resources/749
The Fundamentals of Freeze Drying modules are presented by Dr. Steve Nail, Senior Research Scientist at Baxter Biopharma Solutions
for modeling and analysis of lyophilization/freeze-drying:
1. Interactive Lyocalculator
Lyocalculator models product temperature and sublimation rate during primary drying for specified chamber pressure, shelf temperature and container/product properties.
Excel-based lyocalculator (Courtesy Dr. Serguei Tchessalov/Pfizer): Lyocycle_design_and_transfer_template_Breckenridge_workshop--Pfizer_Original.xls (2 MB)
Abridged version for training by Dr. Tong Zhu: 170727-Lyo-Calculator_Training-Added_Macro_Solver.xls (66 KB)
2. Pressure Variation Calculator https://pharmahub.org/resources/pressurevar
simulate variation of pressure within product chamber for specified chamber pressure, shelf size and drying rate rate.
1) LyoHUB's Best Practices Paper, "Recommended Best Practices for Process Monitoring Instrumentation in Pharmaceutical Freeze Drying" can be accessed at http://link.springer.com/article/10.1208/s12249-017-0733-1
1. Developing Transferable Freeze Drying Protocols Using Accuflux® and a MicroFD®
Authors: TN Thompson (Millrock Technology, Inc.), Quiming Wang (Millrock Technology, Inc.), Cindy Reiter (Millrock Technology, Inc.)
2) "Progress in Vacuum Pressure Measurement" Talk by Dr. Martin Wuest (Inficon) https://pharmahub.org/resources/756
ABSTRACT: For many years standard vacuum pressure measurement sensors consist of capacitance diaphragm gauges, Pirani heat transfer gauges as well as ionization gauges. Development has progressed from passive gauges with a detached controller to combination gauges with integrated electronics. Market demand from industry continues to force the development of smaller, cheaper and better process sensors. Better in this context means the sensors must survive the harsh industrial process conditions for longer, measure faster and with better reproducibility. In the area of vacuum pressure metrology new developments are occurring in national measurement institutes and universities. The pressure is determined by measuring the refractive index. I will present some of the recent developments.
3) "Continuous Freeze Drying" Talk by Jos Corver (RheaVita) https://pharmahub.org/resources/792
ABSTRACT: The guidelines of FDA’s PAT mention the need for continuous processing in pharma to achieve a mechanism of 100% control of process and product quality. Freeze-drying is one of the ‘missing links’ in the chain of pharmaceutical manufacturing. Current Freeze-drying is a very slow process and in order to achieve a continuous process there is a need for drastic increase of process speed. RheaVita developed a route towards such increase and also developed physical prototypes to demonstrate and further develop the scientific background. Throughout the development exercises, a scientific way of working has been adopted involving modeling and experimental verification. From the earlier phases onwards, PAT tools have been developed and employed, finally leading to a concept where all process steps are in closed-loop control. The presentation will illustrate some highlights of this effort which started effectively in 2013.