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CPPT 9010: Facility Design & Operation

D.I.T. DT275

Masters in Chemical andPharmaceutical Process Technology

17th December 2009

Clement Farrar

BA BAI MSc MIEI

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Lecture Overview

1) General Support Utilities

2) Water

3) Clean Steam

4) Waste

5) CIP & SIP

6) Autoclaves

7) Washers

8) Solution Transfer

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1) Support Utilities

What are Support Utilities?

Why do we need Support Utilities?

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Support Utilities Essential Utilities

Clean Steam Generators WFI Generators RO Skids Potable Water Process Air CIP Skids

Other Utilities Glycol Instrument Air CO2 O2

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Clean Steam (CS)

Clean Steam is generated with Clean Steam Generators by the distillation of RO or WFI

Clean Steam is used for sanitization

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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

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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 Dioxide CO2 Carbon Dioxide is used to maintain the desired level of oxygen It is sparged through the reactor vessels via the oxygen/

carbon dioxide distribution

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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

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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 levelAir Handling

System

Production RoomWith

DefinedRequirements

SupplyAir

OutletAir

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Process Waste Treatment

Process Waste must be treated prior to discharging from site

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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

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2) Water

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Water Overview

Utility Water Clean Water Softened Water System RO (Reverse Osmosis) Water System WFI (Water for Injection)

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Utility Water Plant Flow Chart

Utility WaterStorage Tank

Utilities Water

User 2

User 3

User 4

Softened WaterPlant

User 1

User 5

Inlet from Local County Council

Distribution Pumps

Sodium HypochloriteStorage Tank

&Dosing Pumps

Chlorine Analyser

Chlorine Analyser

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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

plantFor generation of RO & WFIBoiler feed water

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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

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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

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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

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Soft Water Plant - Sample Schematic

Water Softener

#1

Water Softener

#2

Water Softener

#3

Multi Media

#3

Multi Media

#2

Multi Media

#1

Soft Water

Storage Tank

To Site Distribution

Distribution Pumps

Bisulfite Addition

Hypochlorite Addition

Hardness Analyser

Utility Water Inlet

User 1

User 2

User 3

User 4User 5

User 6

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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

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Reverse Osmosis Water Generation - Sample Schematic

RO STORAGE

TANK

RO LOOP RETURN

RO DISTRIBUTION

SOFT WATER BREAK TANK

ACTIVATED CARBON FILTER

0.5 um FILTER

RO MEMBRANES

PUMP

RE-CIRCULATION TO TANK

SOFT WATER

SOFT WATER BREAK TANK

ACTIVATED CARBON FILTER

0.5 um FILTER

RO MEMBRANES

PUMP

RE-CIRCULATION TO TANK

SOFT WATER

RO Generation Capacity 17 m3/ hr

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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

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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

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WFI Generation Still

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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

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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

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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

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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

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3) Clean Steam

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Clean Steam Overview

What is Clean Steam? Where is it Used? How is it Made? Pipe Work & Components Standards

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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 withRegulatory requirement to comply to biological and chemical

specifications for these systems

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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

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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)

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Clean Steam - How is it made?

These are the 1850Kg/Hr & 2800Kg/hr clean steam generators

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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

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Clean Steam Trapping

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

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Clean Steam - Pipe-Work & Components Steam separators (to help improve steam dryness).

Clean Steam Separator

Typical Pressure Reduction Set

Trap Set Arrangement

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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

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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

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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

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4) Waste Neutralisation

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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

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Waste Neutralisation Functionality

Waste Neutralisation Tank - Critical Parameters pH Temperature Availability of Oxygen Flow to Sewer

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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

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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 reached the Sewer Valve can be

interlocked to maximise the usage of the capacity of the tank on occasions

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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!

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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 discharge limit are defined as

pollution events. Consequence of continual license excursions would lead

to fines and even a site shutdown

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Waste Neutralization Plant Review

IPCL

Operational Issues

Suspended Solids Volumetric

Flow SPOF Mech & Civil

Repairs Required

Waste Neutralisation System

Tank

Maintenance

Design

Verification

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5) CIP/ COP

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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

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CIP Cycle

Used on Lines & Vessels Lines are generally quick as they are small in

comparison with vessels CIP cycles use hot chemical solutions

CIP 100 solution (KOH, base or caustic) CIP 220 solution (HCl, Acid) Blow down steps RO & HWFI rinses

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CIP CycleSteps in the Cycle are typically: Step 1: Reverse Osmosis (RO) water rinse Step 2: Blow down Step 3: Caustic solution rinse Step 4: Blow down Step 5: RO rinse Step 6: Blow down Step 7: Acid solution rinse Step 8: Blow down Step 9: Hot Water for Injection (HWFI) rinse Step 10: Blow down

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Question

1) Do we need to CIP a vessel if we are going to transfer the EXACT same solution in it again?

2) Why?

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GMP Expectations 21 CFR 211.67 Thorough and reproducible cleaning of equipment and

transfer lines is required to prevent malfunction or contamination that would alter the quality and purity of the drug product beyond the established requirements.

21 CFR 211.182 Logs of equipment use and cleaning must be maintained.

21 CFR 211.68 Automation of the equipment is permitted, but must be

subject to routine calibrations, preventative maintenance and inspections.

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GMP Expectations FDA expects companies to have written procedures

(SOP’s) detailing the cleaning process used for equipment.

The cleaning cycle will remove product residue as well as cleaning solution from surfaces coming into contact with the product.

Companies must validate each cleaning cycle for all pieces of equipment.

Companies must have written procedures detailing the validation process of cleaning cycles.

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Advantages of Automated CIP Equipment that has been CIP’d receives less wear and

tear than items which are cleaned manually. CIP is more efficient than manual cleaning because the

vessel has uniform and consistent cleaning. CIP means improved safety for personnel since they

have no contact with heated chemical solutions. Labour required for cleaning is reduced. Production may be increased through reduction of down

time. Automated technology allows documentation of the

cleaning performance which can be monitored

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CIP Hazards You have to break into lines and certain vessels to begin

a CIP circuit This can lead to incorrect fittings and loose connections

(e.g. transfer panels, spool pieces, filter housings). Pressurised air blow (2 bar). Pumps produce (5 bar) when operating Temperatures are in excess of 70oC Heated chemical solutions at high pressure

(HCl & KOH).

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COP (Clean Out of Place)

Used on small portable vessels and small pieces such as filter housings and spool pieces (COP Bath)

Carried out in designated COP station The equipment is cleaned by a combination of heat,

force and chemical exposure.

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COP - Small Vessel

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COP - Bath

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COP - Spool Piece

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Question

Why not manually wash small parts?

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COP - HazardsHazards are the same as for CIP but also include; The need to hook up flexi hoses to the portable vessels

to begin circuit This can potentially lead to incorrect fittings and loose

connections The vessels and their connections may be hot after

cleaning (PPE must be worn) Disconnecting hoses and the emptying of vessels may

expose technicians to small volumes of hot cleaning solutions

Manual handling of small vessels

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6) SIP (Steam In Place)

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SIP Overview

Automated steaming system Kills microorganisms and

spores Releases massive energy when

the saturated steam comes into contact with the microorganisms

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SIP Operation One temperature probe (at the coldest

point of the system) controls the sterilisation time - CONTROLLING TEMPERATURE PROBE

Other temperature indicators (TI’s) are monitored to ensure uniform sterilisation. These TI’s are ‘trapped’ to ensure adequate condensate removal

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SIP Parameters STEAM - must be saturated (in equilibrium with it’s

condensate) Saturated steam at a minimum temperature of 121.1ºC Temperatures above 127 oC can affect probe

performance and damage gaskets PRESSURE

15 psig TIME

Validated for different pieces of equipment using biological indicators ( BI’s )

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SIP Key Functions

Air Removal

Condensate Removal

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Air Removal Steam/ air mix will result in

unsaturated steam (saturated steam required to kill microorganisms)

Performed by bleeds at high points

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Condensate Removal

Condensate also creates an unsaturated steam condition

Condensate will cause cool spots

Removed by low point Traps

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Typical SIP Cycle Set up system per SOP Assure adequate signage Vent air up to 100o C then close exhaust Heat up system to temp [>121.10C] Hold system at validated temperature Cool down system slowly - maintain positive pressure

by adding sterile air to avoid vacuum formation Maintain system closed and sterile under positive

pressure

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SIP Hazards

High temperatures

Pressurised steam - can blow off loose connections

Unlagged plant in high risk areas

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SOP (Steam Out of Place) Used on small portable vessels

Cycle parameters are the same as for SIP

Carried out in designated SOP station

Key functions (e.g. air removal) are the same as for SIP

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SOP - Hazards

High temperatures

Pressurised steam - can blow off loose connections

Potential for technicians to be exposed to pressurised steam

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SOP Recommendations

It’s essential to have someone check the set-up PRIOR to starting a SOP cycle

Inform co-workers PRIOR to starting a cycle

Watch for leaks at the beginning of the cycle - this is when most leaks start

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6) Autoclaves

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Autoclave

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Autoclave Overview Designed for steam sterilisation of dry goods (e.g. filter

housings, hoses, machine parts) Steam sterilisation takes place in autoclave under vacuum for

a length of time governed by F0 calculations

F0 calculations give the time taken to achieve desired lethality

rate of bacterial spores at a given temperature of steam

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Autoclave Process Description

Pre-cycle Pre-conditioning Heating Exposure Post-conditioning Equalisation

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Process Description Pre-cycle

Leak test Pre-conditioning

Vacuum Level & Hold and Pressure Level & Hold or Forced Air Removal

Heating Heating Up 1 & 2 Filter heat up

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Process Description Cont.

Exposure Sterilisation

Post-conditioning Vacuum Level & Hold and Pressure Level & Hold or Slow Exhaust

Equalisation

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7) (Parts) Washers

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Washer Function Designed to insure adequate cleaning, rinsing and

drying of product contact surfaces (e.g. Media/ Buffer/ Filling Line Parts)

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Washer Process Overview WFI passes through a heat exchanger before entering the

washer sump The heated WFI is pumped through spray jets on loop

headers designed to cover all areas of items to be washed Addition of detergent via diaphragm pump Steam coils installed in the sump heat the wash solution. Tank mounted on the side of washer stores hot WFI for once-

through final rinse Filtered, heated air is circulated through cabinet during drying

cycle

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Washer Cycle

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Washer Process Description

Prewash Circulated Detergent Wash 2 x Circulated Rinse Non-circulated WFI Rinse Drying

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Washer Process Description - Prewash WFI from supply passes through heat exchanger before being

pumped into washer sump. Hot WFI is circulated through spray jets on loop headers for

specified length of time. Pneumatic ball valve directs water to drain. Cold water is

added to drain solution to prevent damage to drain

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Washer Process Description - Circulated Detergent Wash

Hot WFI Sump fill

Detergent is dispensed to the washer for specified amount of time (Must reach specified conductivity)

Circulation

Drain

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Washer Process Description - 2 x Circulated Rinse As per Prewash

Temperature & Time setpoints variable

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Washer Process Description - Non-Circulated WFI Rinse Hot WFI Storage tank is filled and maintains its fill during

the wash cycle

Steam coils maintain heat in tank

A separate header system is used for final WFI rinse to provide isolation from the circulated water

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Washer Process Description - Drying Dryer air flows through steam heating coil and HEPA filter

before circulation

High volume blower circulates the hot air over items to be dried

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8) Solution Transfer

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Transfer of Solutions

Having made up various solutions/ ingredients….. How do you get a solution made in Tank A into Tank B?

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Transfer of Solutions

Lines

Pumps

Pressure

Transfer panels Let’s look at transfer panels in more depth

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What is a Transfer Panel?

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Transfer Panels

A Transfer panel has a number of ports with hard piping behind them connected to various vessels/ utilities

Ports are connected using U-shaped pipes called ‘Jumpers’

The jumpers create a closed loop connecting tanks/ utilities which can stretch across different areas

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Transfer Panel & Jumpers

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Jumpers

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Question - Transfer Panel Hazards What types of hazards can you think of that are

associated with transfer panels?

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Question - Transfer Panel HazardsWhen transferring solutions,

hazards can include: Incorrect connections Loose jumper connections Breaking/ making connections Pressurised tanks and lines Tank Contents (acids, caustic) Again, the MSDS will contain all info

necessary for providing first aid / spillage control

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QUESTIONS???

clement.farrar@gmail.com