Site Operations Pfizer Cork Ltd., Inchera, Little Island, Cork

Attachment D.1 Site Operations Pfizer Cork Ltd., Inchera, Little Island, Cork IPPCL Application May 2007 Issue No 2 45078720 Attachment D 1 - Site Operations Main.doc

CONTENTS Section Page No 1. OVERALL DESCRIPTION OF THE SITE LAYOUT... 1 2. SCHEDULE 5.16 ACTIVITIES... 2 2.1. Overview... 2 2.2. Process Unit Operations... 3 2.2.1. Solids handling... 4 2.2.2. Reaction... 5 2.2.3. Liquid-liquid extraction... 6 2.2.4. Concentration and Crystallisation... 7 2.2.5. Distillation and Reflux... 8 2.2.6. Filtration... 9 2.2.7. Centrifugation... 10 2.2.8. Drying... 11 2.2.9. Filter Drying... 12 2.2.10. Comminution/sieving... 13 2.2.11. Milling... 14 2.2.12. Packaging... 14 2.3. Process flow diagrams for particular products... 15 2.3.1. Nicorette... 16 2.3.2. Estracyt... 17 2.3.3. PEP (Polyestradiol Phosphate)... 18 2.3.4. Epirubicin... 19 2.3.5. Doxorubicin... 20 2.3.6. CPT-11... 21 2.4. Pollution Abatement Systems... 22 2.4.1. Emissions to Air Abatement... 22 2.4.2. Emissions to Sewer Abatement... 22 2.5. Auxiliary systems... 22 2.5.1. Raw material and waste storage systems... 23 2.5.2. Utility systems... 24 2.6. Change Control... 26 2.7. Laboratory Facilities... 26 2.7.1. Technical Services Laboratory... 26 2.7.2. Quality Control Laboratory... 26 2.7.3. Environmental Laboratory... 27 3. SCHEDULED 11.1 ACTIVITIES... 28 3.1. Solvent Recovery... 28 3.1.1. Overview... 28 3.1.2. Batch Stills... 28 3.1.3. Solvent stripping... 32 4. DEVELOPMENT AND OPERATIONAL HISTORY OF THE SITE... 33 Attachment D 1 - Site Operations Main.doc Page i

CONTENTS Section Page No Attachment D 1 - Site Operations Main.doc Page ii

1. OVERALL DESCRIPTION OF THE SITE LAYOUT The Pfizer site layout is presented in drawing reference number FSK-2023. The Inchera site is situated in an industrial park in an area known as Little Island approximately 6 km east of Cork City. Its north boundary is adjacent to N25 and Bury s Bridge Basin and its south boundary is adjacent to the Little Island s Main Road. In the vicinity of the site there are several other pharmaceutical and chemical operations, most notably Cognis/Henkel which immediately borders the site to the south and east, Pfizer Little Island (formerly Warner Lambert) 100 m to the east, Cara Partners 200 m to the east. There are no residential housing developments, schools or medical facilities in the immediate vicinity of the site. The total site area is approximately 202,746 m 2 (50.1 acres). The main operational area of the site covers approximately 101,200 m 2 (25 acres). The key facilities on site consist of: Administrative offices; Production facilities; A Quality control/warehouse complex; Laboratories; Utilities; A wastewater treatment plant; A maintenance workshop; and Storage areas, including two tank farms. Additionally there are storage tanks for water, sprinkler supply and fuel oil, together with various tanks associated with the wastewater treatment plant, the carbon adsorber and the firewater retention pond. External areas comprise asphalt roadways, concrete yard areas, hardcore areas and grassland. The operational part of the site is located in the south of the site. A fire water retention pond is located in the north-east of the site, with a contractors compound and open land in the west of the site, to the north of the main operational area. The far north of the site comprises undeveloped land containing a small area of woodland designated as a proposed Natural Heritage Area by Cork planning authority due to its value to nesting birds. In addition, there is a mains gas compound located between the canteen and warehouse buildings that is owned and operated by Bord Gais (the national Gas Distribution company). Pfizer site personnel have no access to this compound. Associated with this compound is a way leave over part of the site following the route of the high pressure Bord Gais gas main. There is also a way leave associated with a water main located towards the east of the site. Attachment D 1 - Site Operations Main.doc 1

2. SCHEDULE 5.16 ACTIVITIES 2.1. Overview Pfizer Cork Limited (Pfizer) produces bulk pharmaceutical intermediate active products in batch processes. Any one product is manufactured in well planned campaigns (i.e., a predetermined number of batches with target yields). Various raw materials, largely solids and some which are intermediates from other product manufacturing, are chemically reacted in the presence of carrier organic solvents to produce the active ingredient product. This product is separated, purified and dried. The organic solvents used are called carrier solvents because they, with some exceptions, do not chemically react in the process and are recovered later in the process. There are three production plants OP4 to OP6. All production plants contain various trains of process equipment that are commonly encountered in batch pharmaceutical manufacturing, namely: Solvent manifold systems and solid charging booths; Reactor vessels of varying volumetric capacity; Separation equipment comprising mainly centrifuges and filters; Driers; and Milling equipment. The production plants equipment layouts and design are such that equipment trains can be arranged in such a way as to facilitate multi-product manufacturing. For example, the same reactors and centrifuges can be used for several product campaigns. Processes, which comprise of a number of unit operations connected to each other, are described in section 2.2 and flow diagrams for some of the products currently produced are described in section 3. Monitoring and control of the manufacturing processes is achieved though the use of instrumentation which measure and control, for example, pressures, temperatures, levels, flows, agitator speeds and various analytical properties, as required by the individual processes. Process instrument and motive equipment data is fed to centralised control systems that are monitored 24 hours per day. Attachment D 1 - Site Operations Main.doc 2

The table below presents products currently on the production schedule: Production Area OP4 Products PEP NRC and NCC Estracyt Latanoprost CPT11 Epirubicin Unit Operations Employed Solids handling Reaction Phase separations Liquid-liquid extraction Chromatography Concentration OP6 Idarubicin Doxorubicin Latanoprost OP5 Sutent 2.2. Process Unit Operations Distillation/Crystallisation Filtration/Centrifugation Drying Comminution/sieving Milling Packaging The table below presents description of various process unit operations, aspects of these operations that cause emissions and process control. In addition a schematic diagram for each process is provided. Attachment D 1 - Site Operations Main.doc 3

Process description Emissions Schematic Diagram 2.2.1. Solids handling Processes use solids which are pharmaceutical actives and chemical additives and reagents. Pharmaceutical actives are typically handled in a glove box, which consists of a closed container operating under a small negative pressure in an inert atmosphere. Manipulations are carried out using gloves, accessible through a transparent wall in the container. The charging of a reactor, for instance, requires the docking of a preweighed container and the subsequent discharge into the reactor charging chute. Pharmaceutical actives are also handled using double plastic liners within drums and sluices. Local fume extract hoods are provided at handling stations. A variety of dedicated containers and systems are used for the handling and dispensing of none active ingredients. Emissions to the working atmosphere are prevented during normal operation by the application of a negative pressure within the glove box or extract inlet relative to the surrounding area. Extracted gases are as a minimum HEPA filtered to remove dust particles prior to discharge to atmosphere. A breach in the glove box for instance caused by a tear in a glove, could potentially lead to an emission to the local environment. The mitigation is the negative pressure employed and integrity alarms. In addition, the building provides a secondary containment protecting the outside environment. Attachment D 1 - Site Operations Main.doc 4

2.2.2. Reaction The reactors on site form the core of production. Each of the processes can use one or a number of batch reactors to carry out the various dissolutions, reactions, liquidliquid extractions and concentrations (described below). These reactors are stirred pressure vessels of capacities ranging from a few litres to several thousand litres. In order to promote and control the various chemical reactions, any of the following can be applied: pressure/vacuum, agitation, cooling, heating or refluxing. Two or more reagents (solid, liquid or gas) are brought together within the vessels in order to chemically react with each other and form new compounds. Gaseous emissions from the reactors arise during normal operations as a result of filling, nitrogen purging, heating, evacuation, and due to chemical reaction. Gaseous emissions are routed to appropriate abatement system(s) e.g. condensation, absorption or adsorption prior to discharge to atmosphere. In addition all reactors are protected from overpressure in abnormal circumstances by a relief device (bursting disc and/or relief valve) which would relieve to a vessel and thence to a suitable gaseous abatement system. This arrangement seeks to reduce the potential impact of abnormal operations on the environment. After inerting, the reactor is maintained under a low pressure nitrogen blanket. Reactors are temperature controlled; typically the reactor contents temperature controller setpoint is cascaded onto the jacket temperature controller which will modulate the control valve in the jacket circuit. Where the addition of a material into a reactor causes an exothermic reaction there is a feed-back from the reactor contents temperature controller to the dosing valve. In the event of the reactor contents temperature rising above a pre-defined alarm limit, a predefined shutdown procedure will be effected, resulting in a safe condition being achieved. A high level alarm is installed to prevent overfilling during the charging cycle. In the event of the level rising to this alarm limit the actuated isolation valve( s) in the charge line(s) will close automatically. Actuated process isolation valves will fail to their fail safe position in the event of an electrical power or instrument air failure. Attachment D 1 - Site Operations Main.doc 5

2.2.3. Liquid-liquid extraction This unit operation relies on the unequal distribution of components between two immiscible liquids. The liquid solution (feed) is contacted intimately with a suitable incompletely miscible liquid (solvent), which preferentially extracts one or more components. This results in a solvent lean residual feed solution with one or more components removed (raffinate) and a solvent rich solution containing the extracted solute(s) (extract). A reaction vessel is used for contacting and separation and a receiving vessel to collect the raffinate. In the example depicted the feed and solvent are intimately contacted in the reactor and then allowed to settle. The solute partitions to the heavier phase solvent which is then transferred by gravity to the receiver. Gaseous emissions arise during normal operation as a result of filling and nitrogen purging. These are ducted to an appropriate abatement system. The extract and raffinate phases will require either further processing, efl1uent treatment or off-site disposal. The reactor contents are allowed to settle and the extract is drained from the reaction vessel until the interface is detected. On interface detection valves will control the destination of the material. The cut off point will be determined by the phase which contains the product and the liquids in use. Where appropriate interface detection instruments will be employed. Attachment D 1 - Site Operations Main.doc 6

2.2.4. Concentration and Crystallisation Concentration of solutes is achieved by removal of solvent from a solution by evaporating the solvent (often under vacuum for temperature sensitive products). The solvent is then condensed and removed from the system. Solids are produced from solutions by either crystallisation or precipitation. Crystalline solids are formed from unsaturated solutions when the solution is evaporated or cooled to below its saturation point. Crystals are also formed by precipitation upon mixing of two solutions, such that the required solid is insoluble in the resulting mixture. Reactors are generally used for concentration and crystallisation processes. Same as Reaction described above. Condensation using low temperature coolant is also used. Key control parameters are temperature, pressure and ph. Reactors are typically temperature controlled by cascading the temperature controller setpoint to the jacket temperature controller, which in turn will modulate the control valve in the jacket circuit. A reduced pressure can also be used during the evaporation process. The pressure is reduced to the desired level by evacuation of the vapour in the head space by a vacuum pump. To maintain the desired pressure within the vessel, the pressure controller in the vent line is cascaded to the vacuum pump pressure controller. The ph is controlled using the analyser installed in the vessel and the automatically controlled addition of either an acid or a base, which is controlled by a flow meter operating an automated valve in the charge line. Attachment D 1 - Site Operations Main.doc 7

2.2.5. Distillation and Reflux Used solvents may be recovered for reuse by separation from each other and from contaminants by distillation. Solvent streams are selected for recovery on the basis of the following criteria: the volume and frequency of generation of the waste stream; the purity constraints for reuse in operations within a particular pharmaceutical process; the ease of separation of the solvent mixtures; and the difficulty of disposal of the spent solvent. Batches of the spent solvent mixtures are heated to boiling in batch or continuous distillation units comprising reboiler vessels, distillation columns, overhead condensers and associated vessels and pumps. Waste fractions from the distillation process are disposed of as described in Section H2. Gaseous emissions are handled in much the same manner as for concentrati on and reaction unit operations A high level switch will automatically close the still fill valve when the high level is reached. This will prevent overfilling. Detection of a high pressure or temperature will cause the steam supply to the still to be isolated via an automated isolation valve in the steam supply line. Safety relief valves will protect against failure of the instrumentation safeguarding systems. Distillate from the still is collected in tanks fitted with a high level alarms. Attachment D 1 - Site Operations Main.doc 8

2.2.6. Filtration Filtration is the separation of solids from a suspension in a fluid by means of a porous medium or screen, which retains the solids and allows the fluid to pass through. A wide variety of filter designs are employed. The solids may be, for example, product (for further processing), by-product, spent material for recovery or disposal. The filtrate may be, for example, product solution; or spent liquors for recovery or disposal. Capacities range up to several hundred kilograms of solids held in a filter device. Gaseous emissions will arise during normal operation as a result of filling, venting, depressurisation and purging operations. These emissions are routed to appropriate gaseous emissions abatement systems. Filtrates and wash liquors will be routed for further processing, recovery or disposal (incineration or wastewater treatment). Solid wastes generated by filtration will be treated as described in section 4. Typically the differential pressure across the filter is monitored. As the cake is deposited on the filter screen the differential pressure will rise. At a predefined differential pressure an alarm will signal the requirement for intervention to prevent the filter screen from blinding. Attachment D 1 - Site Operations Main.doc 9

2.2.7. Centrifugation Centrifugation is the separation of materials by filtration or utilising density differences by the application of centrifugal force. The most common application of centrifuges is a filtering centrifuge for the separation and deliquoring of crystalline material. This operates in a manner similar to the filtration unit operation described above except that centrifugal force is used to aid separation and dewatering of the cake. Centrifugation may include charging, dewatering, washing, and discharge. The operation may be carried out in an inert atmosphere to avoid the oxidation of sensitive products or the presence of flammable atmospheres. Capacities range up to several tens of kilograms of solids held in a centrifuge. Same as for filtration. Centrifugation is carried out in a proprietary equipment package which is supplied with its own instrumentation, control and safeguarding systems. Operation beyond the normal operating parameters will be detected and appropriate alarms generated. In the event of a trip situation occurring the centrifuge will be shutdown to a safe condition. An interface is provided between the supervisory control system and the centrifuge package systems. Attachment D 1 - Site Operations Main.doc 10

2.2.8. Drying Drying is the removal of a liquid from a solid by evaporation. Products and intermediates are dried to remove excess liquid utilising either an agitated dryer or a tray dryer following centrifugation or filtration. In either case a charge of wet solids is made into the dryer and the following physical processes are employed to remove the excess liquid: indirect heating, agitation, vacuum. Vapours removed are condensed and the small resultant liquid flows are sent to the appropriate recovery or disposal system. When the solids are sufficiently dry they are removed to storage. Gaseous emissions arise from the evaporation of liquids. The vapours are condensed. Non-condensed gases are ducted to an appropriate abatement system. The dryers are generally located within their own separate structure in the building to meet cgmp requirements and to contain potential solids spillages. Dryer capacities range up to several tens of kilograms of solid per batch. A dryer is a proprietary equipment package which is supplied with its own instrumentation, control and safeguarding systems. The instrumentation provides the required measurements for monitoring and control. The level of process control varies between manual and fully sequenced. For the latter the control system will execute the correct sequence of operations, for instance; establish vacuum, inert, charge, heat zonally, agitate and cool. Should the dryer malfunction causing an excursion of a measured value, the dryer control and safeguarding system will either alarm only or shut down to a safe condition following a predefined sequence. Attachment D 1 - Site Operations Main.doc 11

2.2.9. Filter Drying A filter dryer achieves the two unit operations of filtration and drying in one piece of equipment. The feed (a solids suspension) enters the filter dryer. The solids are held on the filter media and the mother liquor passes into a waiting receiver. Pressure and/or vacuum may be employed to assist the filtration. When filtration is complete the product is dried and discharged. Filter-dryer capacities range up to over one hundred kilograms of solid per batch. Emissions described in filtering and drying above. However since two unit operations are carried out in one piece of equipment there will be a reduction in the handling and cleaning wastes. The filter dryer is supplied as a proprietary equipment package with its own instrumentation, control and safeguarding systems. The instrumentation provides the required measurements for monitoring and control. The process control will be fully sequenced and will execute the correct sequence of operations, for instance; establish vacuum, inert, charge, filter, heat zonally, agitate and cool. Should the filter dryer malfunction causing an excursion of a measured value, the filter dryer control and safeguarding system will either alarm only or shut down to a safe condition following a predefined sequence. Attachment D 1 - Site Operations Main.doc 12