Module 10: Purchasing a Lyophilizer

1. Module 10:Purchasing a Lyophilizer

2. 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

3. GAMP Qualification Plan

4. 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.

5. Overview

6. Systems To Be Addressed

7. Chamber • 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.

8. 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

9. Door • 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

10. Shelves • 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.

11. 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.

12. 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.

13. Stoppering • 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.

14. 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

15. 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.

16. 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.

17. 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.

18. 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

19. 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.

20. 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.

21. Instrumentation • 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.

22. 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.

23. Sterilization • 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.

24. 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

25. Safety • 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.

26. Utilities • 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

27. Documentation • 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”.

28. Questions 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?

29. 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.