Podcast
Questions and Answers
What is the primary benefit of using freeze-drying for drug substances?
What is the primary benefit of using freeze-drying for drug substances?
Which dosage forms are typically prepared using the freeze-drying process?
Which dosage forms are typically prepared using the freeze-drying process?
What is the first step in the freeze-drying process?
What is the first step in the freeze-drying process?
What does PAT stand for in the context of freeze-drying?
What does PAT stand for in the context of freeze-drying?
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Which factor is crucial for successful drying during the freeze-drying process?
Which factor is crucial for successful drying during the freeze-drying process?
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What is the primary method used in freeze drying to remove water from samples?
What is the primary method used in freeze drying to remove water from samples?
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What risks are associated with freeze concentration during the freeze drying process?
What risks are associated with freeze concentration during the freeze drying process?
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What does PAT facilitate in the freeze drying process?
What does PAT facilitate in the freeze drying process?
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What is the potential consequence of increasing temperature during freeze drying?
What is the potential consequence of increasing temperature during freeze drying?
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How do the eutectic and glass transition temperatures influence the stability of a product during the primary drying phase?
How do the eutectic and glass transition temperatures influence the stability of a product during the primary drying phase?
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What is the significance of evaporation at low pressure in the freeze-drying process?
What is the significance of evaporation at low pressure in the freeze-drying process?
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Explain the relationship between pressure, volume, and temperature in the context of the freeze-drying process.
Explain the relationship between pressure, volume, and temperature in the context of the freeze-drying process.
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In what way does active cooling differ from external freezing methods in large-scale freeze drying?
In what way does active cooling differ from external freezing methods in large-scale freeze drying?
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What complications can arise from not controlling the volume during evaporation in freeze drying?
What complications can arise from not controlling the volume during evaporation in freeze drying?
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Study Notes
Lyophilization
- Lyophilization is a technique preserving drug stability and activity during drying.
- The liquid phase undergoes a solid-to-gas transition (sublimation).
- The process involves drying and vacuum sealing, reducing risk of microbial contamination.
- Solid cake can be easily reconstituted due to the pore structure.
- Chemical integrity of complex molecules is maintained.
Learning Objectives
- What freeze-drying is and its pharmaceutical applications?
- Common dosage forms prepared by freeze-drying?
- How a freeze dryer is designed?
- Types of excipients used for freeze dried products?
- What PAT is and how it is used during freeze-drying?
- Methods to optimize freeze-drying processes?
Powders for Injections or Infusions
- Solid, sterile substances distributed in containers.
- When shaken, they rapidly form clear, particle-free solutions or suspensions.
- Manufacturing method is freeze-drying.
- Contains additional excipients to facilitate the drying process.
Phase Diagram
- Pressure and temperature define whether sublimation or evaporation occurs.
- Successful drying requires both parameters to be tightly controlled.
Process
- Freeze drying processes involve freezing, primary drying, secondary drying, and storage.
- Temperature and chamber pressure are critical parameters during the process.
- Timescales for steps are measured in hours and years.
Freezing
- Freezing is the crystallization of water at reduced temperatures.
- Product temperature (Tp) should remain below the glass transition temperature (Tg) or eutectic temperature (Teu).
- Industry freeze dryers use active cooling, while research models may use external freezing (freezer) plus evaporation energy cooling.
Important Temperatures
- Eutectic temperature – the temperature at which two or more crystalline species melt together as a single compound.
- Glass transition temperature – the temperature where amorphous substances transition from solid to liquid state.
Drying
- Evaporation at low pressure dramatically expands the volume.
- Without a process to reduce volume, pressure cannot be controlled.
- Important formula: p * V = m * R * T = constant.
Freeze Dryer Key Components
- Drying chamber with heating
- Condenser with active cooling
- Vacuum pump
Freeze Dryer Design
- Chamber with vials
- Cascade compressor
- Condenser window
Freeze Dryer Condenser Design
- Sublimation (Endothermic)
- Condensation (exothermic)
- Optimal vapor transport with large valves and short distances between condenser and chamber.
Freeze Drying Risks and Challenges
- Insufficient cooling causing ions and small molecules to melt at lower temperatures.
- Secondary drying before complete evaporation.
- Incomplete drying due to short drying intervals, rapid evaporation, or insufficient vapor transfer.
Freeze Drying Cycle
- Graphs displaying typical vacuum and temperature profiles during freeze drying.
- Shows parameters like vacuum (mbar), shelf temperature (°C), and condenser temperature (°C).
Sublimation
- Density of the solution
- Total water content
- Mass fraction of ice
- Radiation
- Conduction (thermal conductivity & shape of the vial)
- Convection
- Water mass transfer
- Heat transfer coefficient (Kv)
- Fill depth
Limiting Factors - Mass Transfer
- Product resistance (pore size, excipient concentration, compactness)
- Stopper resistance (stopper geometry)
- Chamber resistance (distance to ice condenser, condenser capacity, dryer geometry).
- Loading (ice condenser's capacity to determine maximum possible loads/vial loading).
Limiting Factors - Heat Transfer
- Heat conduction through the product
- Heat convection through the product.
- Heat radiation.
- Factors affecting heat-transfer efficiency are shelf temperature, vial geometry, and equipment loading.
Layer Thickness and Vial Type
- Drying time depends on layer thickness (10 mm ≈ 24 hrs, 20 mm ≈ 48-60 hrs).
- Pre-freezing methods include static (cold air/deep freezer) or dynamic (rotating flasks) methods.
Common Urban Myths
- More lyoprotectants aren't always better; they lower melting point and require deeper cooling.
- Deep vacuum doesn't improve drying efficiency; high gas volume can lead to unstable vacuum.
Excipients
- Excipients are substances added to a pharmaceutical product to aid the drug's processes.
Freeze Drying Changes in the Product Microenvironment
- Changes in solute concentration, pH, chemical gradients, hydrogen bonds with excipients and water.
- Pressure, osmotic changes, and thermal gradients during freezing
Steps and Effects - Freezing
- Shift in pH and high osmotic pressure during freezing increases risk of agglomeration.
Steps and Effects - Annealing
- Ice crystal size affects drying rate.
- Annealing achieved through cycles below Tg to increase ice crystal size.
- Crystal growth reduces biological stability of samples; annealing promotes rapid drying at expense of a more stressed product.
Cryoprotectants
- Inhibition of crystal growth (e.g., glycerol, DMSO).
- Steric stabilization and mechanical support (e.g., surfactants, polyethylene glycol, polyvinyl pyrrolidone, dextran, albumin).
Steps and Effects - Drying
- Sublimation removes product binding partners during drying.
- Example mechanism shows water replacing binding partner for phospholipids in liposomes.
- Hydrophilic molecules like sugars replace water during the process.
Lyoprotectants
- Glass transition temperature of freeze concentrated solution should be below freezing temperature.
- Product temperature should remain 2-3 degrees below glass transition temperature of the concentrated solution.
Formulation Science - Biosimilars
- Biosimilars use the same excipient and dosage form as the reference product, as much as possible.
- Small differences in certain excipients (e.g., human serum albumin) don't preclude biosimilarity if data shows a close similarity to the reference.
Process Analytical Technology (PAT)
- PAT is a set of measurement techniques integrated into process monitoring.
- Important for quality in complex manufacturing environments where high quality is needed.
Steve Jobs and MacFactory
- Manufacturing high-quality medicines requires high quality standards.
- Processes without feedback loops leave errors undetected.
PAT – Feedback
- PAT continuously monitors manufacturing processes using parameters to asses if the processes produce desired quality.
- This is achieved through high measuring speed by using robust, long-running instruments with low maintenance.
Process Understanding
- PAT used to understand processes that influence quality and predicting issues to adjust processes before impacting quality.
PAT – Freezing Point
- The electrical conductivity of the product increases dramatically when changing from solid to liquid phase.
- The freezing point can be determined using the temperature and resistivity curve.
Single-Vial PAT – Electrical Resistance
- Monitoring electrical resistance provides appropriate data for melting detection.
- Electrical resistance increases when going from liquid to solid phase.
- The freezing point can be indicated by recording temperature and electrical resistance simultaneously.
Single Vial PAT – Temperature
- Shows graphs demonstrating product temperature and shelf temperature during the drying process
- Useful data plots illustrating temperature trends during the study.
Single-Vial PAT – Handling Single Vial Sensors
- Conventional sensor units lead to cable spaghetti issues, making handling inefficient.
- Wireless sensor units provide more convenient handling with higher accuracy and sensor positioning options.
Single-Vial or Batch PAT – LyoBalance
- Function principle based on electromagnetic force compensation for precise weight measurements.
- Application ranges from -40-40°C with resolution up to 0.001 g.
- Advantages include integration to LSCplus controller, direct weight measurement, and placement on any shelf position.
Batch PAT – Vacuum
- High vacuum increases sublimation rate but needs rapid recondensation for volume reduction.
- Vacuum stability changes indicate mass transfer issues.
Batch PAT – Mass Spectrometry
- Troubleshooting, method development tool rather than process monitoring.
- Measures gas composition (e.g. water content) to track freeze-drying progress.
- Offers detailed information on drying effectiveness at different temperatures.
Batch PAT – Pressure Rise Test
- Used to determine the end of a process.
- Measures pressure inside the drying chamber and assesses it against the empty system.
- Result is an estimate, not precise measurement.
PAT Summary
- Single-vial PAT: probes measure temperature, probes measure conductivity changes, using microbalances to measure mass loss/transfer.
- Batch PAT: vacuumsensors indicate mass transfer problems , pressure rise test tests for residual water , mass spectrometry performs gas composition analysis.
Check Process – Without Fancy Equipment
- Manual pressure rise test (needle jump test).
- Manually closing a valve, monitoring pressure, and watching for pressure surges/needle jumps to indicate incomplete drying.
Quality Control – Without Fancy Equipment
- Finger test(grinding the dry sample). No crumbs sensed and well-dried samples will feel soft.
- Visual appearance of the “cake”, Checking for good appearance and absence of melting.
- Redispersion, checking for rapid redispersion without sonication or vortexing.
Freeze Drying Process
- Illustrative steps in the freeze-drying process, including the relationship between step number, process steps, explanations, and examples of the steps.
- Includes information like sample temperature and vacuum values.
Freeze Drying Process (continued)
- Step 3, Setting drying time involves consideration of layer thickness in determining the drying time.
- Step 4, Starting secondary drying, involves reducing vacuum to a minimum, verifying it by a pressure rise test
From R&D to Production
- Categorisation of lab, pilot, and production freeze dryers based on processing volumes (2-24kg , 6 - 16kg , 25 - 500 kg).
- Lab scale typically have application-oriented accessories, whilst pilot & production models are fully integrated with production type accessories
Summary
- Freeze drying is a mild drying technique using sublimation of water.
- Freeze dryers maintain controlled temperature and pressure for efficient sublimation processes.
- Potential issues from freeze concentration/microenvironmental changes/increasing temperatures during the process(leading to melting).
- PAT enables improved process monitoring through parameters like conductivity, temperature, and pressure.
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Description
This quiz explores the freeze-drying technique known as lyophilization, highlighting its application in preserving drug stability and activity. It covers various aspects, including dosage forms, freeze dryer design, excipients used, and process optimization. Test your knowledge on this critical pharmaceutical method!
