BOC Edwards Lyomax 28 Lyophilizer 300 sq/ft (28 sq/m) LN2 cGMP Freeze Dryer

OVERVIEW

The freeze dryer control system consists of two levels of control: the Personal Computer (PC HMI) as the higher level control and the Programmable Logic Controller (PLC) as the lower level. Field mounted equipment (instrumentation and actuators) are integrated into the system to control the Lyomax 28 freeze dryer. The freeze dryer is a pressure vessel containing temperature controlled shelves. The shelves are loaded with product from the facility sterile area. The shelves can be cooled to -70°C and heated to +70°C. This shelf heating and cooling is achieved using an immersible electrical heater refrigeration circuits as required by the shelf temperature control PIO loop.

The chamber normally operates under a medium vacuum which is achieved using two dry pumps and a single booster pump. During the sublimation process large volumes of vapor are released from the product and these are condensed on the chilled condenser coils. Condensing the vapor on the condenser coils reduces the vapor discharge and prevents contamination of the vacuum pump. The condenser coils are refrigerated using direct expansion liquid nitrogen (LN2) refrigeration. The condenser coils are refrigerated to an ultimate minimum temperature of -70°C. Controlled sterile room air or Nitrogen bleeds into the chamber to control the vacuum level during the drying steps of the freeze drying cycle. Nitrogen or sterile room air is also used during the initial vacuum release (pre-aeration) and final vacuum release (aeration) stages of the freeze drying cycle.

As this freeze dryer is required to operate in a sterile environment the unit is designed to be steam sterilizable. Steam sterilization of the freeze dryer will cause the internal surfaces of the freeze dryer to be heated to a minimum temperature of 121°c. The freeze dryer is capable of using steam to defrost the condenser coils and melt ice that has formed during the drying steps of the freeze drying cycle, from the product's sublimated vapor. The freeze dryer has also been engineered to include a clean in place (CIP) system which is capable of removing water soluble residue left in the freeze dryer following the completion of the freeze drying cycle.

The control system for this freeze dryer can be divided into the following:

1.         A Lyomaster PC HMI operator interface that initiates manual and automatic cycles. The Lyomaster PC HMI is comprised of Windows XP and lntellution iFix. The PC HMI has multiple screens available to select various operations. The PC HMI collects process data from the PLC, displays it to the operator, and allows the user to enter set points. The Lyomaster PC HMI has six programmable levels of security plus a Master password to give multilevel protection.

2.         An Allen Bradley PLC (Programmable Logic Controller), interfaced with the Lyomaster PC HMI, is used to control the freeze dryer logic and implement the appropriate interlocks, during manual and automatic modes of operation. The system programs are resident in the internal RAM and can not be modified by the operator. The operator does not operate the PLC directly. The PLC operates in the background when the operator uses the PC HMI.

3.         A Lyomaster PC HMI view node (maintenance) with the same functionality of the SCADA PC operator interface.

Chamber

The BOC Edwards shelf freeze dryer (lyophilizer) shall be capable of freeze drying liquid products. The freeze dryer consists of a rectangular chamber, 15 + 1 product shelves, and a horizontal vapor condenser. The main door is mounted, on the clean room side of the chamber, with the hinges on the left-hand side as viewed by the operator. The chamber is loaded and unloaded manually via this door. Illuminated sight glasses are provided on the main door and the wall of the chamber, to allow visual monitoring of the freeze drying process. The sight glass on the main door is remotely illuminated; this means the sight glass does not have a light of its own. When the operator wishes to view the chamber through the main door's sight glass, the operator will push the "Chamber Sight Glass Light" push button on the slave panel in the sterile room. That push button will turn on the light mounted to the other sight glass in the chamber, for a period of 1 minute. The sight glass light that is mounted on the side of the chamber can be turned on manually, by pressing and holding the manual pushbutton mounted in the sight glass light assembly. The chamber, its valves, piping instrumentation and the remainder of the freeze dryer can be accessed from the maintenance side.

The chamber and the main door are fabricated from 316L stainless steel. The chamber reinforcements are fabricated from 304L stainless steel. The chamber and main door are supplied with a cooling jacket, through which water will be circulated for rapid cool down after steam sterilization. All internal corners are radiused for easy cleaning, and to allow draining through the drain located in the bottom of the chamber. The chamber drain is covered with a wire mesh to prevent vials or stoppers, going down the drain and clogging the butterfly drain valve. The chamber is ASME coded with a maximum operating design pressure of 30 PSIG. The chamber is designed to withstand steam sterilization (SIP) and clean in place (CIP). The external surface of the chamber is fully insulated with chloride free, non-asbestos insulation (fiberglass), and covered with polymer foam (armaflex). The chamber is aluminum clad, to protect the insulation.

Shelves

The product shelves have a total surface area of approximately 28 m². The product shelves are located in the chamber. The surfaces of the product shelves and chamber that are exposed to the product are fabricated from 316L stainless steel and the reinforcements are fabricated from 304L stainless steel. The shelf stack consists of 15 product shelves and one (1) compensation shelf, of the same dimension as the other 15 shelves. Each shelf has the dimensions of 1524 x 1219 x 24 mm, before polishing. The standard interdistance space between the shelves is 75 mm. There are three alternate interdistances: 100 mm for 11+1 shelves, 120 mm for 9+1 shelves and 150 mm for 7+1 shelves. The compensation shelf is mounted above the top product shelf, in order to maintain the same thermal conditions that exist in the other shelves. Each product shelf has 2 fences.

The shelves are hollow and contain the diathermic fluid, 1.6 cSt silicone oil. Inside the shelves are baffles that channel the silicone oil through the shelves, in order to provide uniform distribution of heating and cooling to all areas of the shelves. The silicone oil is pumped through the channels, in the shelves, from the heat exchangers, heating element, and pipe system by means of twin circulation pumps. The circulation pumps are mounted parallel to each other, in the shelf fluid circulation system. The pumping duty is alternated between the two pumps, every time an automatic freeze drying cycle is initiated. In the event one pump fails, or there is a drop in operating pressure, that pump will turn off and the other pump will turn on. The silicone oil flows to and from each shelf through flexible stainless steel hoses, which are welded in place at both ends. The flexible hoses are fabricated from 316L stainless steel, as are all components in the chamber that would come into contact with the product.

Heating and cooling of the shelves is controlled by PIO control loops. A visual representation of the heating and cooling system is found on the P & I diagram D-C85-19-06. An immersible electrical resistance heater controlled by a Silicon Controlled Rectifier (SCR) provides the heating. A dual platinum resistance thermo element (TE201 & TE201A) contained in a thermowell welded at the inlet of the shelf manifold is used to measure shelf inlet temperature. The one signal from the shelf inlet manifold (TE201) is sent to the PLC, and the other signal (TE201A) is wired to the chart recorder.

The signal from TE201 of the dual element RTD will provide the process variable, about which the temperature of the shelf silicone fluid will be controlled. The shelf fluid inlet temperature TE201 is used as the process variable because its location provides the quickest and most accurate method for shelf temperature control. The signal from TE201A of the dual element RTD is used to monitor the shelf fluid inlet temperature at the chart recorder. Fifteen thermocouple product probes (TE101-TE115) will be provided to measure the product temperature. The shelves have an operating range from between -70°C to +70°C.

On this unit there is one hydraulic pump for providing shelf movement and stoppering for the shelf stack. The shelf movement is controlled automatically by the PLC during the various automatic cycles, or by an operator using the manual control located on the slave panel in the clean room. The hydraulically operated ram is mounted on top of the chamber. The ram extends down into the chamber and is attached to a pressure plate. The shelf stack is suspended from its pressure plate by a series of connecting rods. The shelves can be individually aligned for the interdistance, by adjusting the stainless steel positioning nuts on the connecting rods. When the ram is extended, its pressure plate moves downward, the shelves lie on top of each other, and the top shelf can be moved into a position to load from the main door. When the hydraulic ram is retracted the corresponding shelves are raised up and the shelf interdistance is increased to its fully configured range.

The manual movement of the ram by the operator is inhibited whenever the main door is open

 The hydraulic shelf positioning ram is encased, inside the chamber, by a flexible bellows, fabricated out of 316L stainless steel. This bellows is provided to prevent any possible contamination of the product by hydraulic oil that may leak through the hydraulic ram seals.