CPPT 9010: Facility Design & Operation

1. CPPT 9010: Facility Design & Operation D.I.T. DT275 Masters in Chemical andPharmaceutical Process Technology 17th December 2009 Clement Farrar BA BAI MSc MIEI

2. Lecture Overview 1) General Support Utilities 2) Water 3) Clean Steam 4) Waste 5) CIP & SIP 6) Autoclaves 7) Washers 8) Solution Transfer

3. 1) Support Utilities • What are Support Utilities? • Why do we need Support Utilities?

4. Support Utilities • Essential Utilities • Clean Steam Generators • WFI Generators • RO Skids • Potable Water • Process Air • CIP Skids • Other Utilities • Glycol • Instrument Air • CO2 • O2

5. Clean Steam (CS) • Clean Steam is generated with Clean Steam Generators by the distillation of RO or WFI • Clean Steam is used for sanitization

6. Water For Injection (WFI) • Water for Injection (WFI) is a raw material (excipient) • Needs to be ‘clean’ - stripped of any inorganics, organics, microorganisms and have low level of endotoxins • Suitable to inject intravenously • Uses include: • Final rinse for CIP’s • Clean Steam generation • Product formulations • Equipment washing

7. Gases • Oxygen O2 • Oxygen is an essential requirement for the growth of cells (in the case of bio-processing) • It is sparged through the bioreactor vessels via the oxygen/ carbon dioxide distribution loop • Carbon DioxideCO2 • Carbon Dioxide is used to maintain the desired level of oxygen • It is sparged through the reactor vessels via the oxygen/ carbon dioxide distribution

8. Other Utilities • Glycol • Glycol is used as the coolant (through vessel jackets) • Glycol is stored in a Process Glycol Surge Tank • Glycol is distributed throughout the process via the Glycol Distribution Lines • Instrument Air • Instrument air is high pressure air which is used to operate actuator valves and does not contact process contact surfaces

9. Air Handling System Production Room With Defined Requirements Supply Air Outlet Air HVAC (Heating, Ventilation & Air Conditioning) • HVAC System • HVAC systems are located in the interstitial places between the building floors • Its purpose is to maintain the heat, ventilation and air conditioning at the desired level

10. Process Waste Treatment • Process Waste must be treated prior to discharging from site

11. Cleaning & Steaming • Before process equipment can be used it must be Cleaned and Steamed (or Autoclaved) • Clean in Place (CIP) • Method of cleaning the process equipment and associated pipe-work using a variety of cleaning agents such as RO Water, Caustic, Acid and WFI • Steam in Place (SIP) • Method of sanitizing the process equipment and associated pipe work by steaming at high temperatures (~121°C) until certain criteria are met and all micro-organisms are killed

12. 2) Water

13. Water Overview • Utility Water • Clean Water • Softened Water System • RO (Reverse Osmosis) Water System • WFI (Water for Injection)

14. Utility Water Plant Flow Chart Utilities Water User 1 Utility Water Storage Tank Chlorine Analyser Softened Water Plant User 2 User 3 Chlorine Analyser Distribution Pumps User 4 Sodium Hypochlorite Storage Tank & Dosing Pumps User 5 Inlet from Local County Council

15. Utility Water Usage • Uses of Utility Water • As utility water in all buildings (for cooling) • Domestic Water Supply to all buildings • Supply to the cooling towers • Chilled Water • Utility water feeds the softened water generation plant • For generation of RO & WFI • Boiler feed water

16. Why do we need ‘Clean Water’? • Water for Injection (WFI) is a raw material (excipient) • Suitable to inject intravenously • Needs to be ‘clean’ - stripped of any inorganics, organics, microorganisms and have low endotoxin • Specification of WFI defined in various Pharmacopeia’s

17. How do we make ‘Clean Water’? • Drinking water is supplied to the facility • Drinking water undergoes a series of purification steps to turn it into WFI • Examples of Purification steps include softening, deionisation, distillation

18. Soft Water Generation • Utility Water supplied to Soft Water plant • Soft Water Generation • Water is softened by removing hardness ions (Ca2+ and Mg2+) present in drinking water • Softener resins replace the hardness ions with sodium ions (Na+) • Soft Water plant also removes particulates from water using multi media filters • Soft Water is dosed with chlorine to control microbial growth

19. Soft Water Plant - Sample Schematic User 1 User 2 User 3 User 4 To Site Distribution User 5 User 6 Multi Media #3 Water Softener #1 Soft Water Storage Tank Bisulfite Addition Water Softener #2 Multi Media #2 Distribution Pumps Water Softener #3 Multi Media #1 Utility Water Inlet Hypochlorite Addition Hardness Analyser

20. Reverse Osmosis (RO) Generation • RO membranes remove dissolved organics and inorganic contaminants from soft water • High pressures drive water molecules to pass from higher to lower concentrated solution • Opposite to osmosis • Achieves good salt reduction (approx 95%) • Requires constant removal of waste stream (concentrate) to optimise performance • Requires routine sanitisation (heating) and cleaning (chemical) to ensure quality

21. RO LOOP RETURN RE-CIRCULATION TO TANK ACTIVATED CARBON FILTER 0.5 um FILTER SOFT WATER RO MEMBRANES RO STORAGE TANK PUMP SOFT WATER BREAK TANK RE-CIRCULATION TO TANK RO DISTRIBUTION ACTIVATED CARBON FILTER 0.5 um FILTER SOFT WATER RO MEMBRANES PUMP SOFT WATER BREAK TANK Reverse Osmosis Water Generation - Sample Schematic RO Generation Capacity 17 m3/ hr

22. Water for Injection (WFI) Generation • WFI generated through distillation • Requires boiling RO feed water and condensing distillate • Phase transfer • Separates dissolved and undissolved impurities from the water

23. Water for Injection (WFI) Generation • Impurities need to be frequently removed (blowdown) to ensure quality • Any microorganisms killed during phase transfer • Endotoxins separated during phase transfer

24. WFI Generation Still

25. Storage and Distribution Systems • Not just generation of ‘Clean Water’ that is important • Storage and distribution systems are equally (if not more) important than generation • USP and EP WFI biological specifications are very high • Bioburden <10 cfu/100ml • Endotoxin <0.25 EU/ml • Storage and distribution systems are designed to minimise microbial growth • High distribution temperatures • Pipework surface finish • Continuous, turbulent flow • Zero dead-leg valves

26. WFI System Use/ Maintenance • The manner in which the WFI distribution system is used/ maintained is also important • WFI is easily contaminated (biologically and chemically) by people • Care required with usage to ensure that WFI specifications are met • Use of IPA • Use of clean autoclaved hoses/ gaskets • Flushing prior to use • Management of the user points

27. WFI Specifications and Sampling Considerations • EP and USP define WFI biological and chemical specifications • Extensive sampling is performed daily on WFI systems to ensure water quality • Daily biological samples • Continuous conductivity and TOC analysers • Heavy metals, nitrates and description test performed weekly • System performance continually monitored to ensure operating within validated range • Investigations required for any out of specifications

28. What is ‘Clean Water’ used for? • WFI can be the most widely used Raw Material at a Pharma Facility • WFI Uses include: • Final rinse for CIP’s • Clean Steam generation • Raw material used for media and buffers make up • Product formulations • Make up water for product contacting CIP’s • Equipment washing • Area Cleaning • Sinks

29. 3) Clean Steam

30. Clean Steam Overview • What is Clean Steam? • Where is it Used? • How is it Made? • Pipe Work & Components • Standards

31. Clean Steam - What is it ? • Pharmaceutical Clean Steam is a pure heat source used in pharmaceutical sanitisations (mostly) • Clean Steam is generally any steam system that is qualified • Routinely monitored and Quality tested. • Have to demonstrate absence of microorganisms in a condensed steam sample • Have chemical specifications that must be complied with • Regulatory requirement to comply to biological and chemical specifications for these systems

32. Clean Steam - What is it ? • Clean steam is simply steam that contains very little impurities when condensed back to water • It is generated and distributed in a way that reduces potential impurities (biological or chemical) from reaching use points

33. Clean Steam - Where is it used? • cGMP Autoclaves (decontamination autoclaves may use Plant Steam) • Manufacturing Process (SIP’s) - throughout all manufacturing areas & processes clean steam is used for sanitisation • Other uses include: • Used in agitator seals in Bioreactors for sterile boundary. • Used to supply HVAC humidification (instead of dedicated hum steam generator)

34. Clean Steam - How is it made? These are the 1850Kg/Hr & 2800Kg/hr clean steam generators

35. Clean steam - Pipework & Components • Clean systems generation & distribution systems are made up of 316L s/s electropolished high purity piping components. • Condensate build up in clean steam systems is to be avoided – it can affect clean steam dryness quality and if left accumulate on distribution systems can present bioburden issues. • ‘Trapping’ – the removal of condensate

36. Clean Steam Trapping Example of Steam Trap: balanced pressure type from Spirax Sarco - there are different sizes and different condensate capacities available

37. Clean Steam - Pipe-Work & Components • Steam separators (to help improve steam dryness). Trap Set Arrangement Typical Pressure Reduction Set Clean Steam Separator

38. Clean Steam Specifications • CS Condensate requirements: Clean steam condensate = WFI quality • Currently no section dedicated to clean steam so clean steam is required to meet current pharmacopia requirements for WFI

39. Construction Guidelines / Best Practices (e.g. ISPE Guidelines) • Clean steam systems are sloped to assist with condensate removal usually in the direction of steam flow - is as per WFI sloped pipework 1:100 • Steam lines should be sized to give a max velocity of 25M/sec - this is again to ensure trapping is not negated

40. Construction Guidelines / Best Practices (e.g. ISPE Guidelines) • Clean steam traps - vertically mounted, steam off takes from top of pipes etc • The material of gaskets used on ASME BPE clamps and valves on clean steam distributions are an important consideration

41. 4) Waste Neutralisation

42. Waste Neutralisation - Overview • Consists of Waste Neutralisation Tank and ancillary equipment • Its function is to treat the Process Waste prior to discharging to the Local Authority Sewer

43. Waste Neutralisation Functionality • Waste Neutralisation Tank - Critical Parameters • pH • Temperature • Availability of Oxygen • Flow to Sewer

44. Waste Neutralisation Functionality • pH • Waste can have a too high or too low pH • pH corrected using H2SO4 for high pH • pH corrected using NaOH for low pH • pH of the effluent is continually adjusted between 6 - 8 • Temperature • Generally if the temperature rises above 37 Deg C, the cooling supply to the re-circulation line heat exchanger is activated and the effluent is cooled

45. Waste Neutralisation Functionality • Availability of Oxygen • It is critical to keep the neutralisation tank oxygenated to avoid the proliferation of Anaerobic bacteria • There are generally air blowers attached to an air jet system located at the bottom of the tank • Oxygen is monitored in the tank and sustained at a level that will restrict Anaerobic zones where anaerobes may grow • Flow to Drain • When the discharge limit is reachedthe Sewer Valve can be interlocked to maximise the usage of the capacity of the tank on occasions

46. Why Waste Must be Treated • The EPA (Environmental Protection Agency) and Local County Council issue a License called an Integrated Pollution Control (IPC) License to every facility to allow the site to go into operation. • Each facility is responsible for continuing to operate within the limits/ requirements outlined in the license. • Each facility should have a monitoring program that includes daily, weekly, monthly, quarterly and annual monitoring events. • Most importantly each site must restrict the effluent discharged from site on a daily basis to the specified limit!

47. Potential IPCL Issues • Too Much Water Being Generated on Site. • Intermittent Elevated Suspended Solids • The waste tank is a great home for Bugs as there can be a constant source of food and ambient temperatures there • Intermittent Elevated Sulphate Concentrations • Dosing Large Volumes of Sulphuric Acid Due to the Alkali Nature of Waste from CIP activities (Caustic Cleans) • Breaches of the effluent dischargelimit are defined as pollution events. • Consequence of continual license excursions would lead to fines and even a site shutdown

48. Waste Neutralization Plant Review Waste Neutralisation System IPCL Operational Issues Suspended Solids Volumetric Flow Mech & Civil Repairs Required SPOF Design Verification Tank Maintenance

49. 5) CIP/ COP

50. CIP/ COP • CIP (Clean In Place) • Automated chemical cleaning system • Fixed vessels and transfer lines • Validated process and procedures • Equipment is cleaned by combination of heat, force and chemical exposure • COP (Clean Out of Place) (Generally for smaller equipment) • Portable Vessels • Small Components (e.g. Manual Valves, Probes) • Miscellaneous Equipment