Industries: Pharma / Biotech

Lyophilization Technology – Practical Application of the Scientific Principles

Course Director: Edward W. Sunbery, R.Ph.

Course Description - Course runs 9:00 to 5:00 both days

This course is designed to provide attendees with a practical approach to understanding the scientific and engineering principles of lyophilization. The topics discussed during the course will be presented to explain the physical, physicochemical, biochemical, and engineering principles of the science and engineering behind modern freeze-drying. The practicality of the course allows the attendees to get a firm understanding of the theoretical applications of freeze-drying and how these can be easily used and applied to their day to day lyophilization projects.

Topics covered will include:

  • History of lyophilization
  • Properties of water and ice
  • Supercooling and supersaturation
  • Phase behavior during freezing
  • Thermal characterization
  • Annealing
  • Visco-elastic properties of amorphous phases
  • Collapse phenomena
  • Vacuum physics
  • Product formulation
  • Heat and mass transfer
  • Cycle development
  • End point determination
  • Residual moisture
  • Process scale-up and sonic water vapor flow
  • IQ/OQ/PQ
  • Process control and optimization
  • Fault finding and problem solving of systems and formulations
  • Freeze dryer mechanical and control systems
  • Recipe development
  • Following the process

Who Should Attend

This two-day lyophilization training course is designed for those in the pharmaceutical, biomedical, medical device/diagnostic, and biotechnology industries who develop and/or produce lyophilized (freeze-dried) products. This includes, but is not limited to, professionals in Quality Control, Quality Assurance, Validation, Pharmacists, Managers, Microbiologists, R&D Groups, Biochemists, Pilot Plant Operators, Chemical Engineers, Production Supervisors, Chemists, Equipment Maintenance, and Mechanical Engineers. The course will also benefit those in other departments who find lyophilization among their responsibilities.

First Day

Module 1: Introduction:

  • Definition-Freeze Drying & Sublimation
  • Advantages
  • Disadvantages
  • Process Applications
    • Pharmaceuticals
    • Nutraceuticals
  • Types of Freeze Dryers
    • Manifold Dryer
    • Tray Dryer
    • Special Dryer Design
    • Specimen Dryer
  • Special Dryer Design
    • Aseptic Production
    • Spray Freezing and Tray Drying

Module 2: Lyophilization Equipment System Components

  • Chamber
    • Door, Shelves, Vapor Valve & Condenser
  • Vacuum System Pumps
    • Rotary Vane, Mechanical Blower, Piston, Liquid Ring
  • Refrigeration
    • Components – Compressor, Condenser, Expansion Valve, Evaporator
    • Compressor Systems
  • Sensors
    • Thermocouples
    • Resistant Temperature Detectors
    • Thermistors
    • Thermal Gauge (Thermocouple gauges – Pirani)
    • Capacitance Manometer
    • Dial Pressure Gauges
    • McCloud Gauge (Manometer)Resistance Manometer or Thermocouple Vacuum Gauge or Hastings Gauge
    • Thermal Diode Laser Absorption Spectroscopy

Module 3: Basic Principles Supporting Freezing Drying

  • Freezing Drying
  • Atmospheric Pressure
  • Vapor Pressure
  • Evaporation & Condensation
  • Boiling Point
  • Boiling Point and Atmospheric Pressure
  • Freezing or Melting Point
  • Freezing, Melting or Ice Point
  • Eutectic point
  • Osmotic Pressure
  • Freezing Point Depression
  • Particle Impact on Boiling & Freezing Point
  • Eutectic Point of Solutions

Module 4: Regulatory Rationale

  • 1906 Food and Drug Act-Purity
    • Adulterer Food and Drugs
    • The Jungle by Upton Sinclair & Cocaine in Coca Cola
  • 1938 The Federal Food Drug and Cosmetic Act-Safety
    • Safety Before Marketing
    • Elixir Sulfanilamide with diethylene glycol kills 100 people
  • 1962 Kefauver-Harris Amendments-Efficacy
    • Effectiveness based on controlled clinical studies before marketing
    • Thalidomide tragedy
  • Process Validation Definition & Written Procedures
  • Pre-Validation Studies
    • Define Process Requirements
    • Identify Factors Impacting Process Efficiency
    • "Worst Case" Assessment
    • Identify Sampling and Test Plans
    • Process Cycle Evaluation
    • Analytical Validation
    • Finished Product Testing

Module 5: Solution Development

  • Product Definition
    • Quality Product Profile
      • Defined Dosage Form
      • Content per Vial
      • Route of Administration (IV, IM, SC or inhalation)
      • Reconstitution Time
      • Concentration Delivered
      • Head Space (inert gas)
      • Final Presentation (Device)
      • Shelf Life
      • Post Reconstitution Stability
      • Biocompatibility
    • Product Formulation
      • Available Data Review
      • Materials Characterization-Crystalline or Amorphous, Melting
      • Routes of Degradation and Excipient Characterization
      • Container Closure Selection (vial, stopper seal)

Module 6: Freezing Development

  • Freeze Drying Process
  • Solution Freezing Characterization
  • stage Microscopy
  • Subdivision-Optimal & Maximum Fill
  • Fill Volume & Formulation Issues
  • Closure Selection – Design & Vapor Flow
  • Freezing
  • Freezing Salt Solutions
  • Freezing Sugar Solutions
  • Nucleation
  • Crystal Formation
  • Uncontrolled Nucleation – Product Yield and Quality
  • Freezing Techniques

Module 7: Package Selection

  • Packaging Components
  • Types of Containers
  • Packaging Component Qualification
  • Fill Volume and Formulation
  • Closure
  • Closure Formulation Issues
  • Closure – Hot and Cold Temperature Related Issues
  • Seal Selection-Crimping inside or outside the chamber
  • Seal Crimping Issues
  • Component Preparation
  • Packaging Identification & Critical Packaging Controls
  • Packaging Stability Summary-Kinetics and Rate Processes
  • Analytical Methods Summery
  • Product Stress Testing
  • Antimicrobial Effectiveness Test
  • Container Closure Integrity Study

Module 8: Primary Drying Sublimation

  • Container – Closure-Fill Volume and Flow Issues
  • Primary Drying
    • Vacuum-Partial Pressure & Evaporation Rates
    • Heating – Requirements, "Eutectic" & Foaming
  • Product Control
    • Shelf Heating Requirements
    • Drying Time
    • Drying Temperature
    • Temperature Measurements
    • Indications of Sublimation End Point

Module 9: Secondary Drying – Desorption

  • Sublimation End Point
  • Secondary Drying Heating
  • Secondary Drying End Point-moisture between 1% to 3%
    • Determination of Residual Moisture
      • Loss on Drying (Gravimetric Method)
      • Karl Fisher
      • Thermogravimetry and Thermogravimetry / Mass Spectrometry

Second Day

Module 10: Process Overview

  • Lyophilization Process Overview
    • Component Preparation
    • Solution Preparation
    • Solution Filtration
    • Aseptic Subdivision
    • Freeze Drying
    • Sealing
  • Freeze Drying Process Scale Up
    • Freezing
    • Primary Drying
    • Secondary Drying (desorption)
    • Stoppering Vials
  • Quality Attributes
    • Dose Uniformity-Content Uniformity and Weight Variation
    • Freeze Dried Cake Appearance, Color & Odor
    • Identification, Assay, Purity & Uniformity
    • Reconstitution Rate and Ease
    • Reconstituted Solution pH
    • Reconstituted Solution Clarity & Particulate Matter
    • Inert Gas Head Space
    • Sterility & Endotoxins
  • Technology Transfer Summary Report
    • Development Summary
    • Formulation
    • Critical Manufacturing Controls
    • Packaging & Critical Packaging Controls
    • Critical Product Attributes
    • Packaging Stability Summary
    • Analytical Methods Test Summary
    • Product Stress Test Report
    • Antimicrobial Effectiveness Test
    • Container Closure Integrity Study
    • Cleaning Considerations and Requirements
    • Material Safety Data Sheets

Module 11: Installation Qualification

  • Installation Limits
    • Verification of Receipt Versus Specification and Vendor Manuals
      • Equipment – Capacity, Control and Design
      • Site Utilities – Gas, Water, Power
      • Automation – Wiring & Loop Checks
      • Calibration-Time, Temperature, Pressure
      • Safety & Environmental
  • Objectives
    • Equipment Evaluation – Calibration, Maintenance, Critical Features
    • Written Procedures – Calibration, Maintenance, Monitoring, Control
    • Documentation Requirements
      • Engineering Drawings, Schematics, Specifications
      • Details on Connecting Utilities & Safety Specifications
      • Calibration Procedures & Preventative Maintenance SOP's
      • Equipment, System, Facility Cleaning SOP's
      • IQ Report – Installation Meets Intended Design
    • Installation Qualification Check List
      • As-Built Schematics & Instrument List
      • Alarm , Interlock & Security Checks
      • Preventative Maintenance Procedures
      • Spare Parts List
      • Materials in Product Contact
      • References to Supporting Documentation
    • Installation Qualification
      • Chamber, Door ,Shelves, Vapor Valve, Condenser
      • Vacuum System
      • Refrigeration Systems
      • Computer Control Systems (Compliance Issues)
      • Clean in Place – Design & Utility Service
      • Steam in Place – Design & Utility Service
    • Installation Qualification Report

Module 12: Operational Qualification

  • Reproducible Limits
    • Critical Functional Requirements
      • Valve Sequencing (analysis – piping & installation drawings)
      • Process and Safety Alarms
      • Test Run Analyzing Unit Operation Functions
    • Documentation – SOP's
      • Equipment Operation, Utilities & Systems Impact on a Process
      • Correct Equipment Operation and Monitoring
      • Diagnosis of Improper Equipment Performance & Corrective Actions
      • Change Control Procedures – Following Qualification
    • Confirm Equipment Installation Qualification Status
      • IQ Report – Reviewed and Approved
      • Operators Trained on Equipment Operation
    • Operational Qualification Check List
      • List of Components Qualified to Run & Sequence of Operation
      • Test Time Encompasses Typical Operating Time
      • Rationale, Description & Purpose Provided for Each Test
      • Test Method – Description, Set-Up & Performance
      • Test Tools – Calibration Status
      • Sampling Strategy, Critical Parameters Tests & Acceptance Criteria
    • Operational Qualification Protocol
    • Specific Functional Tests
      • Shelf Temperature Heating & Cooling Capability
      • Vacuum System Capability – Blank Off & Leak Rate
      • Condenser Temperature – Capability, Accuracy & Distribution
      • Sublimation Rate Tests – Choke Point & Max Sublimation Rate
      • Shelf Stoppering Device
      • Clean in Place-Riboflavin – Spray Ball Coverage
      • Steam in Place-Temperature Rates and Distribution

Module 13: Preventative Maintenance

  • Vacuum System
    • Back Streaming
    • Oil Levels & Contaminated Pump Oil
    • Blank Off Pressure & Vacuum Integrity Test
  • Refrigeration Systems
    • Contaminated Compressor Oil
    • Expansion Valve
    • Refrigerants
    • Discharge Pressure
    • Non-Condensable Gas
  • Shelves
    • Hydraulic System

Module 14: Performance Qualification

  • Mimic Typical Production Run
    • Condenser Defrosting
    • Clean in Place
    • Steam in Place
    • Vacuum Integrity Test (Leak Rate Test)
    • Shelf & Condenser Cooling
    • Bulk Solution Manufacturing, Aseptic Filtration and Subdivision
    • Chamber Loading
    • Freezing
    • Primary Drying
    • Secondary Drying
    • Stoppering
    • Chamber Unloading
    • Sealing Stoppered Vials
    • Inspection – Specific Process Limits

Module 15: Process Validation

  • Validation Parameters
    • Manufacturing Validation
    • Cleaning Validation
    • Computer Validation
    • Analytical Validation
    • Sterilization Validation
  • Process Validation Life Cycle
    • Process & Facility Design
      • Defined Formulation
      • Freeze Drying Cycle
      • Freeze Drying Cycle Linked to Specific Equipment
    • Facility & Equipment Preparation-Commissioning, IQ, OQ and PQ
    • Validation Study-Evaluation, Sampling, Testing & Reproducibility
    • Continuing Evaluation
    • Change Control-Changes do not Impact Product Quality

Module 16: Equipment Trouble Shooting

  • Pressure
    • Typical Operating Pressures
    • Potential Pressure System Failures
      • Vacuum Pump
      • Leak Test Failure
      • Vacuum Set Point Failure at Primary Drying
      • Vacuum Control Variability
      • Instrumentation
  • Temperature
    • Typical Operating Temperatures
    • Potential Cooling / Heating System Failures
      • Environmental Considerations-Facility & Utilities
      • Compressor Starting & Operation (no cooling or heating)
      • Shelf Temperature Uniformity
      • Shelf Temperature Control at the Set Point
      • Shelf Temperature Heating Slow & Lags Set Point
      • Condenser Set Point Control > ± 10°C
    • Back Streaming
    • Temperature Instrumentation
  • Compressor Discharge Problems
    • Discharge Pressure Too High
    • Discharge Pressure Too Low
    • Shelf Hydraulics Problems
  • Fast or Slow Operating Response
    • Chattering During Operation

Module 17: Case Studies of Failed Product

  • Rule of Thumb for a Failure Investigation
    • Packaging Change
    • Raw Material Change
    • Seasonal or Shift Differences
    • Temperature & Pressure Instrument Calibration

Module 18: Case Studies of Failed Process

  • Case # 1: Out of Specification – product with high moisture content
  • Case # 2: Incomplete Primary Drying
  • Case # 3: Product Separates from Container During Freeze Drying
  • Case # 4: Insufficient Solids or Bulking Agents
  • Case # 5: Product Foaming and Melt Back during Primary Drying
  • Case # 6: Freeze Drying Graph of Temperature and Pressure Readings Following Warming Beyond the Eutectic Point
  • Case # 7: Freeze Drying Graph of Temperature and Pressure Readings Following Warming Beyond the Eutectic Point
  • Case # 8: Freezing Drying Graph of Temperature and Pressure Following Cake Shrinkage or Collapse

Learning Objectives

Upon completion of this course, attendees will have a clear understanding of both the scientific and practical principles behind the formulation and development of lyophilized products. Additionally, participants will gain a firm understanding of lyophilization equipment including system operation, system components, system maintenance, system troubleshooting, IQ/OQ, and system validation. Attendees will also gain practical experience in applying what they have learned by working through several case studies in failed products and cycles. This course is presented in a very practical manner, so attendees will be able to quickly apply what they have learned to their lyophilization projects.

Testimonials

"The lyophilization training course has great technical and very informative material to understand the science behind lyophilization process and the potential problems that may occur during production." Ella H., QA Manager, Gilead Sciences
"The Course Director was very knowledgeable and his real life experiences made the course that much better. He knows what he is talking about!" Kevin D., Director of Manufacturing, J&J
"Since I don't operate the machines or design product cycles I came to this course not knowing what to expect. The result of the course and discussions with instructors and attendees has given me the inspiration to become involved with the freeze-drying processes at my company in the future. The discussions not only gave technical information but brought the processes to my level of interest." Dan M., Bioreagents Technologist, Instrumentation Laboratory
"This was a very good review/introduction to lyophilization. I didn't have much background in any of this when I arrived, but now I feel like I can begin to ask the right questions and to focus on our particular application of freeze drying." John C., Bioreagent Technologist, Instrumentation Laboratory