Site Operations Pfizer Cork Ltd., Inchera, Little …Attachment D.1 Site Operations Pfizer Cork Ltd., Inchera, Little Island, IPPCL Application Attachment D 1 - Site Operations Main.doc

Attachment D.1 Site Operations Pfizer Cork Ltd., Inchera, Little Island, IPPCL Application

Attachment D 1 - Site Operations Main.doc

Attachment D.1

Site Operations

Pfizer Cork Ltd., Inchera, Little Island, Cork

IPPCL Application

May 2007 Issue No 2

45078720

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Page i

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

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Page ii

CONTENTS

Section Page No

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1

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 m2 (50.1 acres). The main operational area of the

site covers approximately 101,200 m2 (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.

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2

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.

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The table below presents products currently on the production schedule:

Production

Area Products Unit Operations Employed

PEP

NRC and NCC

Estracyt

OP4

Latanoprost

CPT11

Epirubicin

Idarubicin

Doxorubicin

OP6

Latanoprost

OP5 Sutent

Solids handling

Reaction

Phase separations

Liquid-liquid extraction

Chromatography

Concentration

Distillation/Crystallisation

Filtration/Centrifugation

Drying

Comminution/sieving

Milling

Packaging

2.2. Process Unit Operations

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.

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4

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 pre-

weighed 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.

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5

Process description Emissions Control Schematic Diagram

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, liquid-

liquid 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 pre-

defined 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.

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6


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.

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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.

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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.

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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.

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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.

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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 pre-

defined sequence.

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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 pre-

defined sequence.

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Documents

Site Operations Pfizer Cork Ltd., Inchera, Little …Attachment D.1 Site Operations Pfizer Cork Ltd., Inchera, Little Island, IPPCL Application Attachment D 1 - Site Operations Main.doc