module 10 purchasing a lyophilizer l.
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Module 10: Purchasing a Lyophilizer. Module 10 Purpose and Objectives. Module Purpose: What to put into a User Requirement Specification Module Objectives: After this module, you will be able to Write the URS Read the Function Specification. GAMP Qualification Plan.

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Module 10: Purchasing a Lyophilizer

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module 10 purpose and objectives
Module 10 Purpose and Objectives
  • Module Purpose:
    • What to put into a User Requirement Specification
  • Module Objectives:
    • After this module, you will be able to
      • Write the URS
      • Read the Function Specification
user requirement specification
User Requirement Specification
  • Permits multiple vendors to bid from the same document.
  • URS makes it the vendor’s obligation to assure that his system meets your requirements.
  • Start with an overview, then use a systems approach to list your wants.
  • Round vs. Rectangular
  • 1 door or 2
  • Rounded corners / 316L / Ra 25 or better
  • ASME certified for 30 psig
  • Insulated (chloride-free non-asbestos)and Cladded
    • How much insulation: Enough for no visible condensate.
  • Floor sloped to drain / drain screen.
  • Tri-Clamp validation port(s) – where and what size
  • All gaskets to be silicone or EPDM.
  • No grease or lubrication on gaskets (including door)
  • Fitted for CIP / SIP and all instrumentation TBD.
chamber connections
Chamber Connections
  • All welded ports are sloped to drain
  • Deadleg ports are to be shorter than 6 pipe diameters.
  • Steam must go through all ports of entry.
  • Thermocouples to be located inside the chamber (how many, type, wire size).
  • Welds ground smooth and polished.
  • Bioseal
  • Which side has the hinge?
  • Auto-locking – Type of lock
  • Gasket detail
  • Safety Interlock? Over-ride?
  • Vision Port(s)? Light?
  • Pizza Port
  • Sample Thief
  • Tri-Clamp ports
  • 316L and 25Ra or better
  • Radiant shelf on top
  • Minimum shelf clearance
  • Shelf latching
  • Edge guards
  • Heat transfer fluid is circulated within and between shelves with corrugated SS tubing between shelves.
  • Both Shelf IN and Shelf OUT thermocouples report.
  • Shelves to hold any set from -50 to +60 + 1C even when the condensers are on.
shelves cont
Shelves (cont)
  • Cooling and Heating rates proceed at > 1C for empty shelves.
  • Shelves are flat within 0.5 mm and sufficiently stiff so as not to flex during stoppering.
heat transfer system
Heat Transfer System
  • Minimum of 2 Heat Transfer Systems – condenser coils and shelves.
  • Silicone or Lexsol
  • Fluorescent dye in medium
  • Fast fluid circulation – minimum 20gpm (water rating)
  • Pump suction and discharge pressure gauges are installed in both systems
  • N2 pressurizes the expansion tank.
  • Expansion tank has a level indicator, input and relief valves, and low fluid drain.
  • The system has a safety thermostat.
  • Top down or bottom up?
  • Automatic or Manual hydraulic acivation
  • Adjustable pressure 4 to 25 psi per vial
  • SS bellows around piston rod
  • Manual operation from either side (clean room or utility area) – in addition to automatic operation.
  • Safety switch to prevent operation with the door open.
  • Safety override switch to permit operation with the door open. Override must be momentary contact.
  • Top down systems may need to activate ram during primary to prevent shelf creep.
condenser s
  • SS 316L and Ra 25 or better with rounded corners for cleaning.
  • Internal or External
  • Capacity must be sufficient to hold the ice from a one inch depth of water over the total shelf area. Round vs. Rectangular
  • ASME certified for 30 psig
  • Insulated (chloride-free non-asbestos) and Cladded
  • Floor sloped to drain / drain screen.
  • Tri-Clamp validation port(s) – where and what size
  • All gaskets to be silicone or EPDM.
  • No grease or lubrication on gaskets including condenser door or manway access.
  • Fitted for CIP/SIP
  • Sight glass into condenser
condenser cooling system
Condenser Cooling System
  • Direct Expansion vs HEX Fluid
  • Minimum condenser temp? -65 or lower
  • Minimum cooling rate? 10 minutes from +5 to -65 is normal.
  • Condenser temperature is read by two type T thermocouples located one on each inlet outside of condenser. i.e. for 2 each compressor there must be a condenser T.
refrigeration system
Refrigeration System
  • Redundant compressors or not?
  • If redundant, then how is duty cycle shared?
  • Refrigerants R404A or R507 or ? No CFCs.
  • The systems are supplied with the maintenance gauges, standard high/low pressure cutout switches, motor winding over temperature protection, interstage subcooler, low oil control, oil separator, dryer, shell-tube water condensers with a water control valve, heated suction accumulators, and a refrigerant sight glass.
vacuum break
Vacuum Break
  • Automated choice of air or N2.
  • There is an in line sterile filter housing suitable for installation of a hydrophobic filter
  • Filter housing and piping has automated shut-off valves to support “in place” filter integrity testing. Required piping ports are also provided
  • If vendor chooses to provide the test equipment, then
  • All aeration tubes (including air filter) are designed to be sterilized up to the SIP block valve with no piping dead legs greater than 6 pipe diameters, and are pitched in order for condensate to drain.
  • Vacuum level control at the set point within the product chamber should be maintained through a time proportional PID loop and associated nitrogen bleed valve.
  • An inert gas inlet port is to be located in the mechanical space with automatic valves to switch from steam to gas after sterilization.
vacuum system
Vacuum System
  • Minimum of a 2 stage vacuum pump.
  • The pump must be equipped with an isolation valve between the pump and ice condenser to prevent possible back streaming of vacuum pump oil when the pump is de-energized.
  • A foreline connection port for leak detection equipment
  • System blank off should be less than or about one milliTorr.
  • Pump down to 100 mTorr in about 20 minutes or less in a clean dry system.
  • Ultimate chamber vacuum with product must be < 50 mTorr.
  • System leak rate of <0.02 mbar-liter / sec. Chamber volume less all included steel and with the isolation valve closed will be provided. Condenser volume less all included steel will be provided.
  • A Roots pump will be utilized as a vendor option, based on need to meet pump down times
mechanical systems
Mechanical Systems
  • Materials of Construction with Certifications
  • Orbital Welding on SIP/CIP with boroscope inspections
  • Valves to be weir-diaphragm type with EPDM diaphragms
  • CIP should be removable with sanitary connections.
  • All lubricants to be FDA approved and disclosed.

Weir-diaphragm valve.

electrical wiring
Electrical & Wiring
  • Equipment voltage shall be 480 volt, 3-phase, 3-wire with neutral and ground, 60 Hertz. There must be single point of connection for each independent skid with distribution thereafter.
  • All electrical enclosures will be NEMA 12 (indoor and protected from liquid splash).
  • Flexible liquid tight conduit harnesses will be used for final connections to aid in servicing/removing.
  • Control wiring will be numbered, corresponding with the wiring diagrams, on each end.
  • Where possible, instruments will be 4-20mA, otherwise 0-10VDC.
  • List each desired instrument.
    • e.g. Capacitance manometer (2 ea) 0-2000 mTorr range
    • Pirani Gauge (1)
    • Capacitance manometer (1 ea) 0-100 torr range
    • Thermocouples
    • Etc.
  • List the exact location of each instrument
  • Explain how instruments should function within the control sequence.
control system
Control System
  • The Control system, loaded onto a workstation must come with full backups and licensing. There must be a 21CFR Part 11 compliant HMI that operates within a Windows XP environment.
  • Data must be exportable to an Excel spreadsheet.
  • PLC control by Allen-Bradley
  • A panel view 300 (for example) will be provided on the clean room side to facilitate stoppering, start pre-programmed cycles, view existing conditions, and break vacuum.
  • Explain how the cycles should operate and provide a sequence of event.
  • Say what is to be alarmed and how the alarms should operate.
  • The freeze dryer chamber and ice condenser can be sterilized with saturated steam at up to 124°C
  • The shelf package must operate during sterilization to assure sterility of the crevices in the ram bellows.
  • Detail the sequence of operations.
  • Detail the sterile filtration sequence and
  • Require the sterile filter housing to be approximately at shoulder height for ease of service.
  • Require a water ring pump and a dry chamber post sterilization.
clean in place
Clean In Place
  • Vendor to Provide
    • Size of the sanitary connection for hook-up.
    • Required water flow rate
    • Required water pressure
  • Assure that steam for sterilization will be routed through the CIP piping.
  • Assure shelf activation during CIP
  • Over-pressure: Sanitary safety relief valves rated for 25 PSIG are to be mounted on both the chamber and the condenser.
  • Operation with the door open: A position sensor or alternative automatic mechanism must be installed in the product chamber door, which prevents the steam inlet valve from opening unless the door is closed.
  • Piping insulation
  • Over-current trip devices, etc.
  • Vendor to specifiy
    • Steam requirement in lbs/hr and psi
    • Electrical requirement in Volts, Phase, Amps
    • Cooling water requirement, GPM and Temp.
      • Conformance to local drain codes.
    • Dry Compressed Air – cfm at pressure
    • Utility room heat removal
    • Drainage – CIP and other – GPM
    • Nitrogen
    • Vacuum Pump Exhaust
  • Require submission of electronic documents in the format that your desire.
    • Autocad
    • Acrobat
    • WORD
    • Excel
  • Require a “submission set” for approval and specify what documents must be in the submission set. (e.g. general arrangement and P&ID).
  • Require adherence to GAMP.
  • Require a “Functional Specification”.

How much will the Lyophilizer Cost?

How much time will the FAT require?

How long will it take to Deliver?

Should I purchase the IQ/OQ from the vendor?

module 10 what to remember
Module 10 What to Remember
  • You will need a User Requirements Specification (URS) in order to obtain multiple bids that are comparable.
  • You will need a URS in order to assure that the Lyophilizer will do what is needed.