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M E M O R A N D U M

DATE: 11 June 2003

TO: Each Board Member

FROM: Elaine Farrell, Licensing and Control

RE: Application for IPC licence from AHP Manufacturing B.V. Trading as Wyeth Medica Ireland for the Wyeth BioPharma Campus at Grange Castle Reg. No. 652

Application Details

Class of activity: 5.6 The manufacture of pharmaceutical products and their intermediates.

2.1 The production of energy in a combustion plant, the rated thermal input of which is greater than 50 MW.

Licence application and EIS received:

25 September 2002

Notices under article 11(2)(b)(ii) issued:

21 November 2002 and 24 March 2003

Information under article 11(2)(b)(ii) received:

18 February 2003,19 February 2003

14 April 2003

Notices under article 14(2)(b) issued:

8 April 2003

Information under article 14(2)(b) received:

15 April 2003 and 8 May 2003

Supplementary material submitted by applicant

8 May 2003, 26 May 2003 and 30 May 2003

Section 97 Notice sent to Sanitary Authority:

21 February 2003

Reply received from Sanitary Authority:

5 June 2003

Company Wyeth Medica Ireland is constructing a multi-product biopharmaceutical Campus at the Grange Castle Business Park, in Clondalkin, Co. Dublin that will be known as The Wyeth Biopharma Campus at Grangecastle.

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The site which consists of 36 hectares, (24 of which will be used initially to accommodate one million square feet of buildings, leaving 12 hectares for further development) is located approximately 12 km west of Dublin City. Planning permission was obtained from South Dublin County Council in August 2000 with alterations and extensions to the existing permitted BioPharma Campus granted in June 2001 and April 2002. An EIS was required and has been submitted with the application. This document was assessed under Article 25 of the EIA regulations and following submission of additional information, was found to be in compliance with the same insofar as it relates to the risk of environmental pollution.

Wyeth the parent company of Wyeth Medica Ireland at Grangecastle is one of the world’s largest research–based pharmaceutical and health-care based products companies. Wyeth has its headquarters in New Jersey and operates in more than 100 countries, employing 55,000 people. Wyeth has operated in Ireland since 1972 employing 1700, at three locations: • AHP Manufacturing t/a Wyeth Nutritionals Ireland, Askeaton, IPC

Reg. No. 395 • AHP Manufacturing t/a Wyeth Medica Ireland (WMI) that will

expand at Grangecastle and was established in Newbridge, Co. Kildare in 1992. The Newbridge facility operates under IPC Licence Reg. No. 581

• AHP Manufacturing BV t/a Fort Dodge Laboratories Ireland, Sligo and operates under an IPC Licence Reg. No. 90.

The facility at Grangecastle will be one of the largest dedicated biopharmaceutical development and manufacturing investment in the world and will create a further 1,300 jobs at both Wyeth Medica locations, Grangecastle and Newbridge. The gross capital cost of the project is 1.6 billion Euro. The products manufactured will be used to make dosage forms for commercial use worldwide. The project involves the construction in two phases, of manufacturing facilities that will be supported by quality control and development facilities. Phase 1 will be completed within 4 years of commencement and Phase 2 is scheduled to be completed within the 10 year life of the planning permission period. Construction commenced in 2001 and is due to be completed in 2005. Operations are due to commence in 2004. All the products are sterile powders, sterile liquids in vials or pre-filled sterile syringes for human use. The site will operate on a 24 hour day, 7 day per week basis. Process Description The Wyeth BioPharma Campus at Grangecastle will manufacture biopharmaceutical products using CHO (Chinese hamster ovaries) or other mammalian cell biotechnology. The facility, which will be one of

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the largest in the world, will be capable of manufacturing any emerging products using this system. The main products proposed at the site include 1) Enbrel® (treatment of moderate to severely active rheumatoid arthritis in adults and juvenile patients). 2) Prevenar- a multivalent pnemococcal conjugate vaccine 3) InductOs® (Recombinant Human Bone Morphogenetic Protein-2) for bone and tissue repair and 4) Refracto® Antihaemophiliac Factor, the first treatment for patients with Haemophilia A formulated in the absence of Human Serum Albumin. Each of the products is currently manufactured in smaller quantities at other facilities around the world. The production of Enbrel® requires notification (to the EPA) under Article 16 of S.I. 73 of 2001 (GMO (Contained Use) Regulations 2001) for the first time use of premises involving the contained use of a Class 1 Genetically Modified Microorganism. The notification was received on 19th September 2002 (GMO Register No. 142) and the consent (subject to conditions) was granted by the Agency on 4th February 2003. The Wyeth Biopharma Campus at Grangecastle will consist of the following main buildings: Drug Substance Building; Drug Product Building; QA/QC/Administration building; Drug Development facility and Pilot Laboratory; Central Utility Building and the warehouse. The Drug Substance building (a five storey structure) will include media preparation, fermentation and purification stages of manufacture. This facility is designed to initially produce recombinant protein product Enbrel. The active ingredient will be manufactured in bulk form within the Drug Substance building incorporating large-scale cell culture with subsequent large-scale purification steps. Enbrel cell culture starts in spinner flasks and is then propagated sequentially through 100 litre, 500 litre and 2500 litre seed bioreactors before transfer to a production bioreactor (12,500 litre). Initially the plant will comprise 6 x 12,500 litre actual (15,000 litre nominal) bioreactors to produce Enbrel- In Phase 2 the production capacity may be increased by 30 %. Each production bioreactor runs for between 10 to 13 days in batch feed mode and is then transferred to a harvest tank and harvested via microfiltration. Once the product has been produced, the cells are inactivated. The required product is then concentrated and purified with acid and base treatment and further filtration and chromatography steps. When it is at the required final concentration and purity, the bulk drug substance (BDS) Enbrel can be refrigerated for up to one month or frozen (at –20oC) for up to a year, prior to aseptic filling and lypholization (freeze drying) in the Drug Product Facility. In the Drug Product Building (a three storey support building), the products are finished. The primary steps of the finishing process are formulation (involving the addition of appropriate buffer and sterile filtration), vial preparation, filling, lyophilisation (rapid freeze-drying), syringe filling, capping and inspection. Enbrel will be supplied in bulk material from the Drug Substance building on site or from the US or Europe. It will be received frozen in 200 litre tanks as preformulated

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material ready for filling and lyophilisation in the Drug Product facility. The bulk active materials for the InductOs product will be supplied from external manufacturers in frozen 3 litre bottles and require formulation prior to filling and lyophilisation. The Strep-Pnemo vaccine (Prevenar) will be imported from Wyeth USA in the form of bulk carrier protein (CRM) and purified serotypes. The process operations for the Strep-Pnemo Vaccine will initiate with conjugation in the Pnemo-Conjugation suite of the Drug Production Facility prior to formulation and filling in the Strep Pneumo suite. Prevenar can be manufactured as 7,9 or 13 valent Pnemo Conjugate vaccine. Of the 13 serotypes, 6 use a chemical conjugation process using DMSO (Dimethyl sulphoxide) and the rest are conjugated using an aqueous sodium phosphate buffer solution. Purification and fill finish for the Refacto product can also be provided in the Drug Product Building.

An initial pilot laboratory (3 storey) will be constructed to support manufacturing in the Drug Substances Building. At a later stage a Drug Development Building- The Irish Development Facility (IDF) will be constructed to serve as a small scale manufacturing unit with two main functions; providing trouble shooting capability for the manufacturing activities of the Drug Substance Building and validating the technologies and procedures required to develop and scale-up the products and processes from the research stage to commercial-scale. It is designed for development at 150 litre bioreactor scale and would include large scale cell culture of CHO or other mammalian cells as well as raw material staging, weight and dispensing, purification steps, media preparation, cell culture suite, harvest suites and waste deactivation.

In the QA/QC building, the in-process testing and final product release testing for those products and raw materials used in the Drug Substance, Drug Product and Drug Development buildings. This building also houses the management and support staff for the Campus.

The Warehouse will hold raw materials, finished product and packaging materials. A portion of the building will be kept between 2 and 8 oC with the second portion at -25oC, a small area/room will be used for freezer storage at –70/80oC and the remainder will be kept at ambient temperature. Material dispensing and QA sampling facilities are also provided within the warehouse function.

A fundamental requirement of the production area is an uninterrupted supply of utility services including steam, cooling water, softened/sterile water and natural gas. The Combined Utilities Building (CUB) houses the primary heating and cooling centres for the campus and the clean water. It houses the boiler room, compressor room, chiller room, electrical plant room, control room and HVAC plant room, central maintenance workshops and goods /passenger lifts.

IPPC Directive

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This installation falls within the scope of category 4.5 (Installations using a chemical or biological process for the production of basic pharmaceutical products) and category 1.1 (combustion installations with a rated thermal input exceeding 50 MW) of Annex Ι of Council Directive 96/61/EC concerning integrated pollution prevention and control.

As a new activity the IPPC Directive requires that the competent authority take account of the general principles set out in Article 3 when determining the conditions of a permit. These require that installations be operated in such a way that:

− all the appropriate preventive measures are taken against pollution, in particular through application of best available techniques (BAT);

− no significant pollution is caused;

− waste production is avoided in accordance with Council Directive 75/442/EEC; where waste is produced, it is recovered or, where that is technically and economically impossible, it is disposed of while avoiding or reducing any impact on the environment;

− energy is used efficiently;

− the necessary measures are taken to prevent accidents and limit their consequences;

− the necessary measures are taken upon definitive cessation of activities to avoid any pollution risk and return the site of operation to a satisfactory state.

The IPPC Directive further requires that the permit must include:

− Measures to ensure that the installation is operated using BAT, meets any relevant EQS and is operated in accordance with the obligations on the operator outlined in Article 3 above.

− Measures to take account of any relevant matters in an EIS.

− ELV’s (and/or equivalent parameters or other technical measures) for those pollutants where significant quantities are likely to be emitted, in particular those substances listed in Annex ΙΙΙ of the Directive.

− ELV’s are to be based on BAT having regard to the location of the installation and the state of the local environment. In all circumstances the conditions of the permit shall contain provisions on the minimisation of long-distance or transboundary pollution and ensure a high level of protection for the environment as a whole.

− A suitable monitoring programme for emissions that will detail the frequency and methodology used and an obligation to supply data to the competent authority.

− Arrangements for emergencies and incidents to ensure safe shut down of installation.

− Any other conditions that the competent authority considers necessary.

The Proposed Determination (PD) as drafted takes account of the requirements of the Directive. In particular, Condition 10 Use of

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Resources provides conditions dealing with water, energy and raw materials use, reduction and efficiency on site. BAT is taken to be represented by the limits set for large combustion plants in Directive 2001/80/EC and guidance given in the IPPC reference document on BAT in common waste water and waste gas treatment/management systems in the chemical sector and in the IPPC draft reference document on BAT for Large Combustion Plant. Large Combustion Plant Directive The Large Combustion Plant Directive 2001/80/EC applies to combustion plants with a rated thermal input of equal to or greater than 50 MW, irrespective of the fuel used (solid, liquid or gaseous). Article 2 (7) of the Directive further states that the directive does not cover plants powered by diesel, petrol and gas engines. Where two or more separate new plants are installed in such a way that their waste gases can be discharged through a common stack, the combination formed by such plants shall be regarded as a single unit. The plant used at Grangecastle comprises CHP (Combined heat and power) units, initially 3 x 26 MW thermal input units with an additional one for future phase, and 3 x 11 MW thermal input steam boilers, which discharge through a common stack. These gas-fired units exceed the 50 MW threshold value in Phase 1 (85 MW rated thermal input) and will increase to 111 MW rated thermal input in Phase 2. The total input rating was calculated from all the combustion sources venting through the common stack but as the emergency generators fuelled by diesel are not used for routine requirements, their input rating was not included. The duty load for the site is calculated as 44 MW during Phase 1 and 98MW during Phase 2. The additional backup capacity is installed due to the high value of the drug products produced. Article 4 (1) of the Directive requires that all licences for the operation of new plants which in the view of the competent authority are the subject of a full request for a licence before 27 November 2002, provided that the plant is put into operation no later than 27 November 2003, contain conditions relating to compliance with the emission limit values laid down in Part A of Annexes III to VII of the Directive in respect of sulphur dioxide, nitrogen oxides and dust. Wyeth have stated that they intend to commission the CHP and boiler units in August 2003. Articles 12,13 and 14 and Annex VIII sets out the procedures for measuring and evaluating emissions from combustion plants. The Proposed Determination as drafted takes into account the requirements of the Directive. Council Directive 1999/13/EC-Solvents Directive The processes carried out fall within the scope of EU Council Directive 1999/13/EC on the limitation of emission of volatile organic compounds due to the use of organic solvents in certain activities and installations. Predicted solvent usage on site, under the definition of solvent in the

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directive, amounts to approximately 73 tonnes per annum in Phase 1 and approximately 92 tonnes per annum in Phase 2. This consists of ethanol (used primarily in the preparation of a storage buffer for purification columns and also in cleaning), acetic acid (used in the preparation of regeneration buffer and an elution buffer in the purification process), DMSO (dimethyl sulphoxide) (used in the chemical conjugation process) and various solvents (including methanol, acetonitrile etc.). The majority of the solvents used in the buffer preparations will be discharged to sewer as part of the COD component of the process effluent with a minor proportion released as fugitive emissions. The use of solvents on-site is within the scope of Annex I of the Directive as ‘manufacturing of pharmaceutical products’ and falls under Activity 20 of Annex IIA –‘manufacturing of pharmaceutical products’ where solvent consumption is greater than 50 tonnes per year. The following conditions have been included as required by the Solvents Directive; Condition 5.7 requires that fugitive emissions shall not exceed 5% of solvent input on an annual basis and Condition 5.8 requires the licensee to prepare a solvent management plan to demonstrate compliance with the fugitive emission limit value.

European Communities (Control of Major Accident Hazards involving Dangerous Substances) Regulations, 2000 (SI 476 of 2000)

In Question 11 of the IPC licence application form the applicant has given details of the assessment of on-site storage with the requirements of SI 476 of 2000. The assessment concludes that under the Seveso II regulations, the site has been classified as a lower-tier establishment and is subject to the requirements of Regulations 8-11 of SI No. 476 of 2000. This is due to the proposed annual storage of 54 tonnes sulphuric acid at the site. The National Authority for Occupational Safety and Health (NAOSH) is the competent authority responsible for administration and enforcement of these regulations.

Proposed Determination

Air:

The main emissions to air from the site will arise from the boilers and CHP (Combined Heat and Power) plant.

The CHP plant will be located within a dedicated building in the CUB yard and will generate electricity using conventional gas turbines with the exhaust gas heat used to generate steam in a heat recovery boiler, thus reducing the steam generating requirements of the central steam boilers located in the CUB building. The CHP plant comprises two CHP units with a provision for a third future unit. The individual stacks from the three CHP units and the three stacks from the conventional steam boilers will discharge through one combined 45 m stack located in the CUB yard. The CHP gas turbine will normally be fuelled by gas but will also be capable of operating on gas oil in the event of a gas

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supply failure. The Steam boilers will normally be fuelled by natural gas but will also be capable of running on gas oil in the event of a gas supply failure.

The Boilers and CHP units will all be fitted with low NOx burners and dry low NOx turbines. These technologies are considered to be BAT.

Impact of Air Emissions on Receiving Environment.

The main component of the boiler/CHP exhaust that will be of concern in relation to air quality is nitrogen oxides. In order to assess the maximum impact of the emissions on the ground level concentrations, air dispersion modelling was carried out.

Two operating scenarios were modelled:

1.The initial installation of a 2 x CHP unit plant with 3 steam boilers each running simultaneously on natural gas at maximum worst case emission values of 88 mg/Nm3 and 75 mg/Nm3 respectively and

2. The planned future build-out of a 3 x CHP unit plant with 3 steam boilers each running simultaneously on natural gas at maximum worst case emission values of 88 mg/Nm3 and 75 mg/Nm3 respectively.

Two different models were used for both scenarios- an ADMS3 model and an AERMOD dispersion model. Both models incorporated information on site location, terrain features, building wake effects, climatological features and emission characteristics. The ADMS3 model incorporates a calculation of the conversion of the NO component to NO2 during the plume dispersion and this is estimated to be between 50 to 80 % conversion.

The AERMOD model assumes 100% conversion of NOx to nitrogen dioxide. The maximum predicted 99.8%ile of one hourly values of nitrogen oxides after expansion (Phase 2) is 50µg/m3 (based on ADMS air dispersion model) and 102 µg/m3 (based on AERMOD air dispersion model). Both of these are below the relevant air quality standard of 200 µg/m3.

The predictions are tabulated below:

98% 1 hour value 99.8% 1 hour value

ADMS3 AERMOD ADMS3 AERMOD

Scenario 1 41 µg/m3 62 µg/m3

46 µg/m3 105 µg/m3

(1999 meterolgical

data)

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Scenario 2 44 µg/m3 73 µg/m3 50 µg/m3 102 µg/m3

(2000 meterological

data)

Standard 200µg/m3 (Note 1) 200µg/m3 (Note 2)

Note 1: Air Quality Standards Regulations (SI No. 244 of 1987) in force until 31/12/09

Note 2: Air Quality Standards Regulations (SI No. 271 of 2002) reducing standard to be achieved by 2010

The ambient air quality in the surrounding area would be expected to reflect the urban/rural intermediate status of the area with inputs from traffic (M50 to the east, N4 dual carriageway to the north and N7 to the south of the site with an expected increase in vehicle emissions when the Outer Ring Road (to link the N7 to N4) is completed close to the site) and combustion gases from domestic houses and commercial premises. Based on data for Zone D (urban-Mullingar) from The EPA Air Quality Monitoring Annual Report 2001, the 98%ile NO2 background ambient concentration in this area could be expected to be approximately 58 µg/m3.

In addition, the use of gas oil in situations where there is an unplanned interruption in the natural gas supply was also modelled using ADMS3 and the following maximum ground level concentrations were predicted:

Parameter

Modelled Impact

Scenario 1

Scenario 2

National Air Quality

Standards

(Note 1)

99.73%ile hourly 108 µg/m3 118 µg/m3 350 µg/m3 Sulphur dioxide

(Note 2) 99.2%ile daily 75 µg/m3 82 µg/m3 125 µg/m3

99.8%ile hourly 54 µg/m3 56 µg/m3

200 µg/m3 Nitrogen Oxides

(as NO2) 98%ile hourly 49 µg/m3 52 µg/m3

200 µg/m3

(Note 3)

Daily (Stage 1)

90.4%ile

4 µg/m3

4 µg/m3

50 µg/m3

PM10

Daily (Stage 2)

98.1%ile

5 µg/m3

6 µg/m3

50 µg/m3 Note 1: Air Quality Standards Regulations (SI No. 271 of 2002)

reducing standard to be fully achieved by 2005 (SO2) or 2010 (Nitrogen Oxides as NO2); PM10:- Stage 1 until 2010; Stage 2 to be met by 1 January 2010.

Note 2: Based on Gas oil at 0.2% sulphur by weight. Further reduction to 0.1% required by 1 January 2008 (1999/32/EC).

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Note 3: Air Quality Standards Regulations (SI No. 244 of 1987) in force until 31/12/09

This model was based on the following data; for boilers-150 mg/Nm3 NOx, 510 mg/Nm3 SO2 and PM10 50 mg/Nm3; and for the CHP units 200 mg/Nm3 NOx, 140 mg/Nm3 SO2, PM10 8 mg/Nm3. Based on this model, no adverse impact is predicted on ground level concentration during the short-term use of gas oil.

The Large Combustion Plant Directive (2001/80/EC) applies to the combustion plant at the Wyeth Biopharma site at Grangecastle, as the rated thermal input of the combustion plant is greater than 50 MW.

For a new plant (which is defined by Article 4(1) of the Directive as one which is subject to a full request for a licence before 27 November 2002 provided that the plant is put into operation no later than 27 November 2003) the emission limits values are laid down in Part A of Annexes III to VI for sulphur dioxide, nitrogen oxides (measured as nitrogen dioxide) and dust. Although natural gas will be used in the plant, the Directive specifies an Elv of 35 mg/Nm3 (at 3% reference oxygen) for sulphur dioxide. The emission limit value specified in the Directive for NOx measured as NO2 (at reference oxygen of 3%) for gaseous fuels and plant with a rated thermal input between 50 and 500 MWth is 300 mg/ Nm3. For dust, the relevant limit is 5 mg/ Nm3 for gaseous fuels.

In the case where Article 4 (2) applies (i.e. for a new plant other than those covered under Article 4(1) of the Directive), the emission limit values specified are 35 mg/Nm3 for sulphur dioxide, 150mg/Nm3 for nitrogen oxides (measured as NO2) for gas-fired boilers (at 3% reference oxygen) and 75 mg/Nm3 nitrogen oxides as NO2 for gas turbines used in combined heat and power systems (at 15% reference oxygen). 5 mg/Nm3 is the emission limit value for dust in this case.

The plant used at Grangecastle comprises CHPs and Boilers all fitted with BAT low NOx burners and low NOx turbines. The proposed emission value of 75 mg/Nm3 nitrogen oxides measured as nitrogen dioxide for the boilers is lower than the relevant emission limit values specified in the Directive and is specified in Schedule 1(i) of the proposed determination as drafted. 88 mg/Nm3 nitrogen oxides measured as nitrogen dioxide was proposed for the emissions from the CHP plant but as this is a new plant, the relevant emission limit value of 75 mg/Nm3 specified in the Directive has been applied in Schedule 1(i) of the proposed determination as drafted.

The relevant sulphur dioxide and dust emission limit values as specified in the Directive have also been applied and should be easily met. Emission limits values (all less than the relevant emission limit values specified for liquid fuels in the Directive) have also been applied in the proposed determination as drafted, for periods of unplanned interruption in the natural gas supply when gas oil is used.

With regard to monitoring requirements under the Directive, Wyeth argue that the gas-fired units exceed the 50 MW threshold value for licensing purposes but are below the threshold of 100 MW requiring

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continuous emissions monitoring. Articles 12,13 and 14 and Annex VIII specify the nature and circumstances of the emissions monitoring.

The key specifications in this Annex are that continuous monitoring for NOx is only required for combustion plant (i.e. those covered under Article 4(2) of the Directive) with a total rated thermal input of 100 MW or more.

Wyeth state that as the use of continuous monitors is not required unless the total thermal rated input exceeds 100 MW and the terms of Article 4(1) (i.e. regarding company having applied for licence by Nov 2002) also apply, the appropriate specified method of measurement is “discontinuous measurements or other appropriate determination procedures in cases where such measures and procedures, which must be verified and approved by the competent authorities, may be used to obtain concentration”. They state that because of Article 4(1) and on the basis of being under the 100 MW threshold that the following phrase from Part A paragraph 2 “where continuous measurements are not required, discontinuous measurements or appropriate determination procedures as approved by the competent authorities shall be used regularly to evaluate the quantity of the above mentioned substances present in the emission”.

They propose to monitor NOx (measured as NO2) and CO annually by flue gas analyser. Annex VIII B specifies that where continuous monitoring is not used the total annual emissions are to be calculated from the specified monitoring procedure. Wyeth have proposed in this case, to determine the daily mass emission by multiplying data relating to the number of hours run each day from the hours run per day in any given combination of firing modes for boilers (recorded and available from the delta V MCS) by the reference performance for each mode. Generator logs could be similarly logged.

This or a similar method of calculation of annual emissions of NOx (as NO2) and carbon dioxide along with quarterly measurement of dust and nitrogen oxides (as nitrogen dioxide) is acceptable initially and will be required to be reported in accordance with Conditions 5.1, 5.11 and also Schedule 1(ii) following agreement with the methodology. However, with the installation of the third CHP unit in future, the thermal rated input at the site will increase to over 111 MW. From this time, continuous monitoring of nitrogen oxides (as nitrogen dioxide) oxygen, temperature, pressure and water vapour will be required in accordance with Condition 5.12 and 5.13.

Other Emissions to Air

Process operations are mainly aqueous based and will not generate any main emissions to air. Very low levels of VOC emissions to air will come from the use of organic solvents in process operations (such as ethanol in purification columns) and QA/QC laboratories and cleaning. Process vents will be exhausted to the atmosphere with appropriate filters installed as required. There are two types of filers; UPLA (which are disposable) and have 99.999% minimum particulate collection efficiency for particulate diameters ≥ 0.12µm in size and

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hydrophobic filters fitted to bioreactor vents which will remove particles and micro-organisms greater than 0.22µm from gases and liquids. Condition 5.3 requires a procedure for the inspection and maintenance of these filters.

Based on Wyeth’s experience at their existing Enbrel manufacturing facilities in the USA, it is not expected that there will be an objectionable odour from the Grange Castle facility. The Enbrel manufacturing does not involve the classic large-scale pharmaceutical fermentation but rather the cell growth is done in small 12,500 litre reactors that are normally closed to the environment. Heat treatment, prior to discharge to sewer also minimises the potential for odour.

In addition to the specific requirements of Conditions 5.9 and 5.10 in relation to the Solvents Directive, a programme for the identification and reduction of fugitive emissions is required as part of the PD as drafted.

Emissions to Sewer:

Emissions to sewer from the site are expected to arise from:

• wastewater arising from process areas

• wastewater arising from utility systems

• sanitary effluent

The wastewater from the process areas can be further divided into

1) fermentation waste – from fermentation and harvest areas of process operations and 2) process wastewater (majority of the waste).

The fermentation waste will be directed to a heat inactivation system prior to discharge to the process wastewater treatment system onsite. The heat inactivation system is a closed system to handle all wastes arising from the fermentation/harvest areas of the production buildings. The waste is subjected to high temperature (90-150 o C) for a set time period (2 minutes) to assure inactivation of all mammalian cell cultures. Inactivated waste is then cooled and pumped to the site process wastewater treatment system. Condition 6.26 of the PD as drafted requires that procedures are put in place for the regular inspection and maintenance of the heat treatment system to ensure that it is functioning effectively at all times.

The production processes at Grange Castle generate a range of aqueous waste streams containing biodegradable organic components and essential nutrients. The following process operations will give rise to effluent:- Drug Substance; Drug Product; Drug development & Pilot Laboratory; QA/QC Labs. The remaining process effluent (other than fermentation wastewater) will be collected in gravity drains and delivered to a process waste vessel. Process waste from the conjugation suites, which may potentially contain the solvent DMSO and spent cyanoborohydride will normally be collected separately and sent to the process wastewater neutralisation system. From mass balance calculation it is indicated that 1.7 µg/l CN (cyanide) will be present in the wastewater. The combined process

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wastewater in addition to utility waterwater (including cooling and boiler blowdown and water regeneration streams from water softening, deionisation and purification water plants) will then be pumped to the site’s wastewater treatment facility for pH and temperature equalisation. The process wastewater treatment system consists of one tank (2019 m3 capacity with a working volume of 1400 m3), recirculation pumps, aeration blowers, a wastewater cooler, educters and inline mixer where pH correction, temperature control and storage is carried out prior to discharge.

Sanitary/domestic sewage will be routed separately from the process drains. In addition to sanitary/foul/domestic wastewaters, there will be additional flows of non-process contacting and non-chemical bearing waters (e.g. condensate from the HVAC condensate) to the domestic effluent line.

Both the process and domestic components will discharge to sewer at the north east of the site at emission point SE1. A monitoring station (TE1) will be provided as the process effluent discharges for the process neutralisation system and will include flow proportional composite sampling. In addition, continuous pH, temperature and flow monitoring will be carried out using automated equipment.

All in-ground process drains will be double contained and terminate in double contained lift sumps. The outer containment shell will have leak detection fitted in the form of high-level alarm switches. The lift sump into which the process lines terminate also acts as a collection sump for the outer containment ring. The segregated wastewater drains from the Drug Substance building and the Pilot Lab/Drug development buildings will be constructed of stainless steel and be suitable for occasional chemical decontamination or steam sanitisation.

Following onsite treatment, the effluent will be discharged to the South Dublin County Council foul sewer and wastewater treatment system (the Dublin Corporation municipal secondary treatment plant at Ringsend) prior to ultimate discharge to Dublin Bay.

Section 97 consent conditions were received from the Sanitary Authority. The maximum process volume permitted is 1850 m3/day with maximum hourly discharge rate of 230 m3/hr. The maximum discharge of combined effluents (which includes the sanitary discharge) will be 2489 m3 per day. The full process loads will not be realised until after Q1 2005.

It is proposed that COD, BOD, suspended solids, total nitrogen, total phosphorus, cyanides and TDS be monitored on a weekly basis. Flow, pH and temperature will be continuously monitored and annual repirometry testing will be required. In addition effluent screening for organic compound and pharmaceutical actives and toxicity testing will be carried out during the first year of operation and thereafter as required by the Agency.

Impact of discharge on receiving sewer and Ringsend MWWTP-

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The design load of the MWWTP facility at Ringsend has been upgraded to deal with a higher nitrogen load and the design loads (2020) are:

BOD 98,400 kg /day Phosphorus (as P)

3,700 kg/day

Dry Weather Flow

4.55 m3/sec Total Nitrogen

15,600 kg/day

Full flow to treatment

11.1m3/sec

Ammonia 9,500 kg/day Average Flow 5.7 m3/sec

The worst case wastewater load from the Wyeth Biopharma Campus at Grange Castle would comprise the following:

BOD (peak)

Nitrogen (peak)

Phosphorus (peak)

Volume

4% of design load

7% of design load

5% of design load

0.5% of design load at Ringsend of DWF

The current average loads are estimated to be 85,650 kg BOD/day.

Wyeth Medica Ireland have investigated the possibility of potential adverse impacts arising from interactions of the effluent discharge from the Wyeth BioPharma Campus at Grange Castle with other effluent present in the SDCC sewage system or MWWTP at Ringsend by examining the properties of the proposed materials in the effluent streams. None of the proposed materials in the effluent stream from the facility are anticipated to have an adverse impact by virtue of reaction with other effluent streams.

With regard to pharmaceutical active ingredients, Enbrel and Prevener are not cytotoxic, pathogenic or available for biological activity outside of the body. They are proteins, which have no long-term persistence in the environment. The proposed determination as drafted requires toxicity and respirometry testing of the effluent within twelve months of the date of commencement of the manufacture of pharmaceutical products and their intermediates.

As the effluent will comprise highly biodegradable cell growth media, it was determined that the best environmental practice option was to pretreat the effluent for heat inactivation and pH correction and discharge it to the MWWTP at Ringsend. In this way it avails of the scale of Ringsend and obviates the need for sludge handling at the site. The environmental outcome is the same regardless of where the treatment occurs. However in the case of Ringsend, the availability of the primary clarification step with biogas recovery from sludge digestors gives the lowest potential energy consumption for this option.

Surface Water:

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There will be one emission point to surface water from the Campus, SW1 which will consist of only uncontaminated surface water run off from the hard surface areas of the site and roof water from the facility. It will discharge to the South Dublin County Council drain and onto the attenuation pond located to the north of the Campus prior to discharge to the Kilmahuddrick stream.

The PD as drafted requires daily visual inspections and regular water quality analysis (including continuous pH and TOC monitoring) to be undertaken at the surface water discharge monitoring point. If contamination is detected the surface water can be diverted to the onsite process wastewater management system. There will also be an oil/petrol interceptor fitted to the surface water line. The SDCC attenuation pond will have a sluice gate fitted to the outlet in order to isolate it from the Kilmahuddrick stream in the event of contamination.

The Kilmahuddrick stream runs along the grand Canal embankment before crossing the canal by a culvert and joining the Griffeen River to the north. There is no classification of the Kilmahuddrick stream or the Griffeen river but the water quality classification of the River Liffey at the stretch of the confluence with the Griffeen river is a rating of 2-3 (moderately polluted). The Griffeen river is not a designated Salmonid river but has important local amenity significance.

It is required that all tank and drum storage areas are bunded to a volume of not less than 110% of contents of the largest tank or drum or 25% of the total tank or drum contents. Drainage from the drum storage areas will be diverted to the spill collection system. A spill collection system will be provided to prevent accidental spillage of bulk chemicals entering the stormwater sewer.

A Firewater Retention Assessment was carried out. In the event of an accidental spillage or fire event the sluice valve on the outlet from the SDCC attenuation pond to the Kilmahuddrick stream can be closed and the contaminated water will be retained for further testing and an alternative disposal option employed, if necessary. Details of this containment system and operating procedure will be required to be submitted to the Agency for agreement in accordance with Condition 9.2.1. Firewater retention is also provided locally at the chemical storage area; drum storage areas, tank truck loading/unloading, tank farm and hazardous waste store and chemical dispensing areas- these areas will be contained for spills and firewater at a centralised retention tank. Available containment volume is 150 m3. The underground tank is double contained in a concrete sump intended for short-term storage of solvent or fuel oil laden firewater. During a fire event, firewater overflow from the bunded areas will go to this tank. The water or chemicals collected will be sampled and pumped to the process wastewater neutralisation tank or to a chemical tanker for off-site disposal.

The impact of the surface water discharge on the receiving environment will be minimised due to monitoring and analysis, segregation of plant operations from surface water collection system, isolation systems, presence of bunding structure and spill control procedures.

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Emissions to ground:

There will be no emissions to ground from this site. There is no history of pollution incidents at the Grange Castle site as it previously was agricultural land and there was no industrial/commercial activity operating at this site prior to construction of the new campus.

A due diligence assessment was carried out at the Grange Castle site. Results of soil and groundwater sampling at the proposed site suggest that there is no major soil or groundwater contamination associated with the site. However, nickel in groundwater was detected at an elevated concentration at three of the five well locations. This is not thought to represent residual contamination in the groundwater but rather it reflects slightly elevated (thought to be naturally occurring) nickel concentrations in the overlying clay soils.

The main receptor of concern at the Grange Castle site is groundwater within the Calp limestone. This is classified by the GSI as a locally important aquifer. Subsoils are generally thin under the site and the groundwater in the limestone bedrock is therefore considered vulnerable to contamination. The Griffeen River tributary of the Liffey is located beyond the western boundary of the site, and may constitute a local receptor for site groundwater. The groundwater is not currently used as a potable water supply but it may be used for agricultural or industrial purposes. The only recorded abstraction well down gradient of the site lies some 3 km to the north at Lucan Golf Course.

The following measures will reduce the potential for groundwater contamination;

• All above ground process piping systems will be located in visible locations over paved/hardstanding areas to protect the soil and groundwater;

• appropriate bunding and containment around the storage and collection areas;

• double containment on in-ground process drains and • concrete hardstanding on all courtyard areas, A network of groundwater monitoring boreholes will be installed (6 locations around the site) and it is proposed to carry out annual monitoring to ensure that activities on site do not have an impact on the ground water.

Waste:

Hazardous wastes that will require disposal offsite include off-specification product material, contaminated product packaging material and solvent waste arising from laboratory activities. Waste, which could be potentially contaminated by biologically active material from the biocontainment areas of the site, will be classified as hazardous wastes. These will include filter elements, product contact items, protective clothing and laboratory waste. All these wastes will be autoclaved on site, which will ensure inactivation of any biological active material and allow the disposal of these wastes as non-hazardous. Steam sterilisation is a recognised procedure for the destruction of all forms of microbial life. The operation of the autoclave

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must be validated, monitored and maintained and records kept on site for inspection by Agency personnel in accordance with Condition 7.8.

Process waste from the conjugation suites, which may potentially contain the solvent DMSO and spent cyanoborohydride will normally be collected separately and sent to the process wastewater neutralisation system. However in the case where there was an abnormal batch or an excessive occurrence of the reactants, the waste DMSO/cyanoborohydride wastewater can be segregated and sent off site as hazardous waste.

General non hazardous waste on site will include uncontaminated packaging waste, and canteen and office waste. Recycling and recovery options will be used where possible.

Solvent waste, laboratory samples, contaminated packaging and waste chemical drums will be removed off-site for specialist recovery/disposal within the State and/or to an incineration facility outside the State. Fluorescent tubes and waste oils will be consigned to a specialist contractor for recycling within the State. Recycling non-hazardous materials such as paper, glass, cardboard etc. will be consigned to appropriate recycling contractors.

While the method of waste disposal/recovery has been described, the specific undertakers had not yet been confirmed. This information will be supplied to the Agency for agreement prior to commencement of the activity. Condition 7 of the proposed determination as drafted requires that waste sent off-site for recovery or disposal shall only be conveyed by an authorised waste contractor.

Schedule 3(iii) requires waste analysis of mixed solvents and aqueous wastes for chemical characterisation (including pharmaceutical active).

It is considered that due to the biotechnology processes utilised by the facility for the manufacture of pharmaceutical products, the quantity of hazardous waste generated is greatly reduced in comparison to equivalent facilities utilising standard chemical synthetic processes.

The conditions in the draft proposed determination require a high degree of control, cross-checking and record keeping to ensure that all wastes are appropriately disposed or recovered.

Noise:

Noise emission limits were incorporated into equipment specification, based on propagation distances to the nearest noise sensitive location. The noise emission design limits for each building were calculated based on achieving the EPA guideline night-time noise limits. Most process equipment is located inside the buildings and is not expected to impact significantly on noise emissions outside the site boundary. Externally located equipment includes cooling towers, externally located pumps and fans, external air handling units and the emergency generator when it is operating. The character of the noise sources is not expected to have tonal or impulsive qualities. The plant is expected to meet a daytime limit of 55 dB(A) and a night time limit of 45dB (A).

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The nearest noise sensitive locations are the houses along Grange View road, which are approximately 135 m from the plant boundary. The main noise emissions in the area are due to local traffic or aircraft. It should also be noted that the Proposed Outer Ring Road linking the N7 with the N4 will pass along the northeastern boundary of the site. The average existing background noise levels are 49 dB (A) daytime and 39 dB (A) night-time.

Measures to ensure compliance with the noise limits include environmental design of equipment and plant to ensure low noise emissions; location of noise sources to take advantage of in-plant screening, design features (attenuating louvers etc.) to attenuate noise at source and the distance and building /berm screening. The licensee is required to conduct a noise survey within six months of commencement of operations.

Use of Resources

Fuel

Natural gas will be used to fuel the steam boilers and the gas turbines of the CHP plant. Gas oil will be used to fuel the emergency generators and firewater pumps. Other equipment will be electrically powered.

Electricity

The maximum demand for electricity is expected to be 23 MW in Phase 1 and 30 MW in Phase 2. The CHP plant will provide 2x 5.2 MW at the site and the balance will come from the national grid. There will also be 2 X 2.2 MW emergency generators in Phase 1 and a third CHP unit in Phase 2.

Water

The water requirements for Wyeth Biopharma are estimated at approximately 2000 m3/day in Phase 1 and up to 4000 m3/day in later phases. This is supplied to the site from the Council main.

Facility Design

The facility was designed with regard to Company energy efficiency and sustainable design standards for new building construction and renovations. These standards adopted by Wyeth in 1991 are based on recommendations from programs such as the USEPA Green Lights and Energy Star programmes and ISO 14001. The Grange Castle facility is designed in a manner that takes advantage of climatic conditions on site to maximise energy efficiency in the control of process temperatures. In addition, it creates capital savings, resulting from smaller pump and piping requirements and long term operating cost savings due to efficient power use. Other examples are:

• Boilers will be fitted with continuous TDS monitoring and blowdown to minimise blowdown water/energy losses. Steam condensate will be recovered for energy and water conservation. Flash steam recovery will be provided on continuous blowdown to reduce water/energy consumption.

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• Tower water and chilled water cooling systems will be provided to optimise cooling water supply temperatures and minimise energy consumption/waste heat rejection and hence tower water losses. Use of once through cooling will be limited to a few minor intermittent loads. Cooling Towers (8 units initially with future capacity for will be fitted with high efficiency drift eliminators (drift losses approximately 0.005%); sidestream filtration and system monitoring will be fitted to limit blowdown to optimal values. The cooling tower treatment programme will permit 5 cycles of concentration to minimise blowdown water losses.

Materials

Materials used in the fermentation processes are natural in character such as carbohydrates, vitamins, peptides and amino acids. Substances used in the manufacture and formulation of products will include common organic compounds such as ethanol, methanol, isopropanol and acetonitrile, inorganic salts such as sodium carbonate, sodium bicarbonate, aluminium chloride and sodium chloride and acids (organic and inorganic) such as hydroacetic acid, and hydrochloric acid. Various chemicals will be used in the water purification process and in the treatment of water for the boilers and cooling towers.

Condition 10.4 of the proposed determination as drafted, requires an assessment of the resources on site and requires the operator to assess performance in terms of resource usage against BAT.

Some List II substances (under The Dangerous Substances Directive and the Groundwater Directive) are used on the site including IMX Amino Acid formulation, IMX powder media, phosphoric acid, (all used in cell culture) urea, (purification), cyclohexamine, sodium hypochlorite, sodium bromide (anti-corrosion and biocides) and one List 1 substance -chloroform (QA/QC solvent). Reduction in List 1 and List II substances is required as part of the EMP.

Habitats

The site of the development is on former agricultural land on the fringe of a suburban housing area. It is bordered to the north and west by a recently constructed access road and to the east by residential housing. There is a significant area of amenity grassland including golf courses to the south of the site. A habitat survey was carried out for the Flora and Fauna Section of the EIS. It was concluded that the area surrounding the site contains mainly highly modified habitats of very low value for flora and fauna, the most significant of which are the network of hedgerows which are of local value.

It is concluded from the assessment of the application, that the activity is not carried out on or located such that it is liable to have an adverse effect on any of the following environmentally designated areas:

• the integrity of a site of community importance as listed under Chapter 1 of SI 94 of 1997 or

• on a site where consultation has been initiated in accordance with Article 5 of the EU Habitats Directive (92/43/EEC) or

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on the integrity of a European site as described in Article 2 of SI 94 of 1997.

There are three areas within 5 km of the site, which are proposed National Heritage Areas.

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Proposed National Heritage Sites within 5 Km radius:

Site Code

Name Distance from site

Significant features

2104 Grand Canal

200m North High diversity of aquatic plants, flora and fauna species found in this area. The opposite-leaved pondweed (Groenlandia densa) which is protected under the Flora Protection Order 1987 occurs in a section of the canal.

128 Liffey Valley

3.5 km north west

It is part of the Liffey Valley Special Amenity Area Order 1990. Species:- Green Figwort (Scrophularia umbrosa) (listed in the Irish Red Data Book Hairy St. John’s Wort (hypericum hirsutum) (Flora Protection Order 1987) and the Yellow Archangel (Lamiastrum galeobdolon) (also listed in the Irish Red Data Book). T

2103 Royal Canal

5 km NW of site

The opposite-leaved pond weed (Groenlandia densa) which is protected under the Flora Order 1987 occurs here. Of particular importance Tolypella intrica, a stonewort listed in the Irish Red Data Book as being vulnerable and only occurring in the Royal Canal in Dublin

The following Proposed National Heritage Sites are within 10 Km radius:

1. Lugmore Glen (site code 1212)-6.5 km south east of site

2. Slades of Saggart and Crooksling Glen (site code 0211) 7 km south of boundary

3. Dodder Valley (site code 0991)-8 km south of site boundary

Glenasmole Valley (site code 1209) is a proposed SAC (Special Area of Conservation) and is located 9.5 km south east of the site boundary. It contains two reservoirs that supply water to south Dublin and is of interest due to the range of habitats it contains including woodland, open water, marsh and clacareous fen. Several rare species including the Green-winged orchid Orchis morio, Yellow Archangel Lamiastrum galeobdolon and Yellow Bird’s-nest Monotropa hypopitys enhance the value of the site.

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Based on the assessment it is predicted that the activities on the site will not have an adverse impact on any sites protected under the Habitats Directive or any European site.

Submissions

No submissions have been received to date

Recommendations:

I recommend that the Proposed Determination be issued subject to the conditions and for the reasons as drafted.

Signed

Elaine Farrell

Licensing and Control

Procedural Note

In the event that no objections are received to the Proposed Determination of the application, a licence will be granted in accordance with Section 85(4) of the Environmental Protection Agency Act 1992 as soon as may be.