Drugsformulations

VALIDATION OF FREEZE DRYER

• “In freeze-drying, water is removed from the frozen state by sublimation, i.e., direct change of water from solid into vapor without conversion to a liquid phase”.
• Used for drying of a no. of products. Especially,

• Blood plasma and its fractionated products.
• Bacterial and viral cultures.
• Human tissues.
• Antibiotics and plant extracts.
• Steroids, vitamins, and enzymes.

WORKING

• Preparation and pretreatment

• preparation of the material (solid, liquid, paste, emulsion) to be processed taking great care not to impede its fundamental properties.

• Freezing

• The freezing step during which the material is hardened by low temperatures. During this very critical period, all fluids present become solid bodies, either crystalline, amorphous, or glass.
• Most often, water gives rise to a complex ice network but it might also be imbedded in glassy structures or remain more or less firmly bound within the interstitial structures.
• Solutes do concentrate and might finally crystallize out. At the same time, the volumetric expansion of the system might induce powerful mechanical stresses that combine with the osmotic shock given by the increasing concentration of interstitial fluids.

• Primary Drying

•   The sublimation phase or primary drying will follow when the frozen material, placed under a vacuum, is progressively heated to deliver enough energy for the ice to sublimate.
• In this period a correct balance has to be adjusted between heat input (heat transfer) and water sublimation (mass transfer) so that drying can proceed without inducing adverse reactions in the frozen material such as back melting, puffing, or collapse.
• A continuous and precise adjustment of the operating pressure is then compulsory in order to link the heat input to the ‘‘evaporative possibilities’’ of the frozen material.

• Secondary Drying

• The desorption phase or secondary drying starts when ice is being distilled away and a higher vacuum allows the progressive extraction of bound water at above zero temperatures. This again is not an easy tack since overdrying might be as bad as underlying.
• For each product, appropriate residual moisture has to be reached under given temperatures and pressures.
• Final conditioning and storage begin with the extraction of the product from the equipment. During this operation, great care has to be taken not to lose the refined qualities that have been achieved during the preceding steps.
• Thus, for vials, stoppering under vacuum or neutral gas within the chamber is the current practice. For products in bulk or in ampoules, an extraction might be done in a tight gas chamber by remote operation. Water, oxygen, light, and contaminants are all important threats and must be monitored and controlled.
• Ultimate storage has to be done according to the specific ‘‘sensitivities’’ of the products (at room temperature, +4oC, -20oC).

The freeze dryer consists of

•  Chamber
•  Condenser
•  Refrigeration Unit
•  Shelf Temperature Control
•  Chamber Pressure Control
•  Vacuum System
•  Hydraulic Stoppering System

Installation Qualification

• Space Requirements
• Electrical Service
• Vacuum Pump
• Manifolds

 

• Prior to Operation

• Damage Claims – WARNING: Do not attempt to pull a vacuum on a freeze dryer with any damage to the clear lids or stainless steel manifolds/chambers. Implosion and potential for injury can occur. If damaged, refer to the User’s Manual for information on shipping damage claims.
• Teflon Coated –  If aggressive acids are to be used within this freeze dryer, Teflon-coated collector chamber is recommended.
• Handling Solvents
• Manifold Installation
• Vacuum Pump Installation
• Vacuum Pump Electrical
• Vacuum Ballast-The vacuum pump’s ballast should remain closed.
• Electrical Connection
• Electrical Grounding

Services required

•  3-phase electrical power
•  Water for compressor cooling and/or Liquid Nitrogen when «cryogenic lyophilizer» option.
•  Hot water or steam for de-icing
•  Compressed air for valve actuation
•  Air/N2 for vacuum release
•  Water for CIP
•  Steam for sterilisation

LIQUID NITROGEN

• Liquid nitrogen can be used either as a low-temperature solution, for example, to trap organic solvents, or as the main cooling medium for both the shelves and the condenser.
• The advantages of liquid nitrogen are as follows:

• Better reliability
•  Eliminates costly maintenance on the compressor
•  Eliminates the need for electricity and cooling water for compressors
•  Cooling power is constant throughout the temperature range.
•  Reduces the space needed for the installation
•  Eliminates noise problems

FreeZone Freeze Dry System IQ/OQ Document

Equipment Location __________________________

FreeZone Ser. No.__________________________

Model No.__________________

User Protocol _________________

Revision (or Date published) __________

Contact (print name):________________________

Title: _____________________________

Operational Qualification

• Automatic Mode

• With the freeze dryer system at ambient temperature, turn the Main Power Switch ON. Press the button labeled “Refrigeration Auto.”

• Power to Vacuum Pump

• When the freeze dryer collector temperature reaches –40oC, the vacuum pump should start.

• Purge Valve Option

• If equipped with the Purge Valve option, the Purge Valve should remain closed until the collector temperature reaches –40oC.

• Refrigeration Effectiveness
• Verify Displayed Temperature

• The temperature indicated on the LCD display is measured at the outlet of the collector coil. The value was calibrated at the factory by correlating its reading with that of a reference gauge attached to a thermocouple. The J-type (red/white) thermocouple can be accessed outside the bottom of the insulated collector chamber.

• TemperatureWave Display

• The temperature “wave” graph of indicator lights on the control panel is a quick reference of the collector temperature. Verify these lights are operating properly.

• Vacuum Leaks

• Verify that the system is leak-free by continuously running the vacuum pump with the refrigeration system ON.
• The rate at the freeze dryer without samples achieves a low level of vacuum, (less than 13 x 10-3 mBar), is dependent upon many factors: Inside volume & surface area of the system. Cleanliness or cleaners used on the interior. Condition & size of the vacuum pump.  Period of time the parts have been exposed to environmental conditions. Based on the freeze dryer’s displayed vacuum level, the freeze dryer should reach its lowest level in less than 18 hours.

• Vacuum Wave Display
• Verify Displayed Vacuum
• Defrost Option

• If the freeze dryer is equipped with a defrost heater, check its operation. With the refrigeration switches OFF, press the “defrost” button ON.

Routine Maintenance

• Vacuum Grease

• Vacuum grease should be applied to rubber components as required. In general, vacuum grease should be the first step in troubleshooting vacuum leaks. Thin layers of grease are adequate for all seals. Only use grease specially formulated for low vacuum service.

• Vacuum Pump Oil

• The vacuum pump oil should be changed as needed. Change oil that appears cloudy or discolored. At a minimum, oil should be changed every 1000 hours of service. An alarm can be set on the freeze dryer to alert personnel when 1000 hours of operation has been reached

• Inspect for Wear & Damage

• Interior metal surfaces for corrosion due to acids2d Refrigeration System Cleaning At least annually, will the refrigeration condenser be cleaned of dust that would restrict free airflow? (include in the preventive maintenance schedule)

Personnel Training

• User Training Related to Equipment

• Are personnel familiar with: All the buttons and displays on the front; Collector capacity limits before defrosting; Defrosting and draining methods; Safe handling of solvents drained; The various alarms on the control panel; The use of vacuum grease; Opening, closing, and venting sample valves; Cleaning of the freeze dryer and neutralization of acids?

• User’s Manual

Performance Qualification

• Once the freeze dryer has been checked for proper installation and operation, its performance can be validated.
• The performance validation should be designed to meet the specifications and accuracy required of the application.
• In general, this requires establishing acceptance criteria, making several runs and testing the results with calibrated equipment and qualified personnel.
• PQ  INCLUDES…

• SHELF HEATING RATE
• SHELF COOLING RATE
• SHELF TEMPERATURE CONTROL
• CONDENSOR COOLING
• SYSTEM EVACUATION RATE
• PRESSURE CONTROL
• LEAK TEST
• SUBLIMATION RATE
• CONDENSOR CAPACITY

SAFETY PRECAUTIONS

• Solvents used in the freeze dryer may be flammable or hazardous. Users are required to wear proper PPE.
• Do not attempt to chip ice off the collector coil.
• Never attempt to start the vacuum pump when there is liquid in the collector chamber.

 MAINTENANCE

• Clean up all spills; remove liquids from the chamber.
• Clean lid and gasket using a soft cloth, sponge or chamois and a mild, non-abrasive soap or detergent.
• Check oil level of the vacuum pump. It should be between MIN and MAX.
• If oil shows cloudiness, particles or discoloration, drain the pump and replace with fresh oil.
• Utilization of acids requires immediate cleaning and neutralization after a run.