Transcript No Slide Title

CPPT 9010: Facility Design & Operation
D.I.T. DT275
Masters in Chemical and
Pharmaceutical Process Technology
17th December 2009
Clement Farrar
BA BAI MSc MIEI
1
Lecture Overview
1) General Support Utilities
2) Water
3) Clean Steam
4) Waste
5) CIP & SIP
6) Autoclaves
7) Washers
8) Solution Transfer
2
1) Support Utilities
3

What are Support Utilities?

Why do we need Support Utilities?
Support Utilities
4

Essential Utilities
 Clean Steam Generators
 WFI Generators
 RO Skids
 Potable Water
 Process Air
 CIP Skids

Other Utilities
 Glycol
 Instrument Air
 CO2
 O2
Clean Steam (CS)
5

Clean Steam is generated
with Clean Steam
Generators by the
distillation of RO or WFI

Clean Steam is used for
sanitization
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
6
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
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
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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7
Other Utilities

Glycol
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Instrument Air
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8
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 is high pressure air which is used to operate
actuator valves and does not contact process contact surfaces
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
Air Handling
System
Supply
Air
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Production Room
With
Defined
Requirements
Outlet
Air
Process Waste Treatment

10
Process Waste must be treated prior to
discharging from site
Cleaning & Steaming

Before process equipment can be used
it must be Cleaned and Steamed (or
Autoclaved)

Clean in Place (CIP)
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Steam in Place (SIP)
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Method of cleaning the process
equipment and associated pipe-work
using a variety of cleaning agents such
as RO Water, Caustic, Acid and WFI
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
2) Water
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Water Overview
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Utility Water
Clean Water
Softened Water System
RO (Reverse Osmosis) Water System
WFI (Water for Injection)
Utility Water Plant Flow Chart
Utilities
Water
User 1
Chlorine
Analyser
Utility Water
Storage Tank
Chlorine
Analyser
User 2
User 3
Distribution Pumps
Sodium
Hypochlorite
Storage Tank
&
Dosing
Pumps
Inlet from Local County Council
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Softened
Water
Plant
User 4
User 5
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 &
 Boiler feed
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water
WFI
Why do we need ‘Clean Water’?
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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
How do we make ‘Clean Water’?

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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
Soft Water Generation

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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
Multi
Media
#3
Multi
Media
#2
Multi
Media
#1
Utility Water
Inlet
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Bisulfite
Addition
User 1
User 2
User 3
User 4
User 5
To Site
Distribution
Water
Softener
#1
Water
Softener
#2
User 6
Soft
Water
Storage
Tank
Distribution
Pumps
Water
Softener
#3
Hypochlorite
Addition
Hardness
Analyser
Reverse Osmosis (RO) Generation

RO membranes remove dissolved organics and inorganic
contaminants from soft water
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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
Reverse Osmosis Water Generation Sample Schematic
RO LOOP
RETURN
RE-CIRCULATION TO TANK
ACTIVATED
CARBON FILTER
SOFT
WATER
0.5 um
FILTER
RO
MEMBRANES
PUMP
SOFT WATER
BREAK TANK
RE-CIRCULATION TO TANK
ACTIVATED
CARBON FILTER
SOFT
WATER
RO
DISTRIBUTION
0.5 um
FILTER
RO
MEMBRANES
PUMP
SOFT WATER
BREAK TANK
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RO
STORAGE
TANK
RO Generation
Capacity 17 m3/ hr
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
22
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
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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
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Storage and distribution systems are designed to minimise
microbial growth
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Bioburden <10 cfu/100ml
Endotoxin <0.25 EU/ml
High distribution temperatures
Pipework surface finish
Continuous, turbulent flow
Zero dead-leg valves
WFI System Use/ Maintenance
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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

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EP and USP define WFI biological and chemical
specifications
Extensive sampling is performed daily on WFI systems to
ensure water quality
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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
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
 Regulatory requirement to
must be complied with
comply to biological and chemical
specifications for these systems
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Clean Steam - What is it ?
32

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
Clean Steam - Where is it used?


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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)
Clean Steam - How is it made?
These are the 1850Kg/Hr & 2800Kg/hr clean steam generators
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Clean steam - Pipework & Components
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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
Clean Steam Trapping
Example of Steam Trap:
balanced pressure type from
Spirax Sarco - there are
different sizes and different
condensate capacities
available
36
Clean Steam - Pipe-Work & Components

Steam separators (to help improve steam dryness).
Clean Steam
Separator
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Typical Pressure
Reduction Set
Trap Set
Arrangement
Clean Steam Specifications

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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
Construction Guidelines / Best Practices
(e.g. ISPE Guidelines)
39

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
Construction Guidelines / Best Practices
(e.g. ISPE Guidelines)
40

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
4) Waste Neutralisation
41
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

42
Waste Neutralisation Functionality

Waste Neutralisation Tank - Critical Parameters
 pH
 Temperature
 Availability
of Oxygen
 Flow to Sewer
43
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
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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
Waste Neutralisation Functionality

Availability of Oxygen
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Flow to Drain
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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
When the discharge limit is reached the Sewer Valve can be
interlocked to maximise the usage of the capacity of the tank
on occasions
Why Waste Must be Treated
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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!
Potential IPCL Issues

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Too Much Water Being Generated on Site.
Intermittent Elevated Suspended Solids
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Intermittent Elevated Sulphate Concentrations
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The waste tank is a great home for Bugs as there can be a
constant source of food and ambient temperatures there
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
Waste Neutralization Plant Review
Waste Neutralisation System
IPCL
Operational
Issues
Suspended
Solids
Volumetric
Flow
SPOF
Design
Verification
Tank
Maintenance
48
Mech & Civil
Repairs
Required
5) CIP/ COP
49
CIP/ COP

CIP (Clean In Place)

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
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
50
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
51
CIP Cycle
Steps in the Cycle are typically:
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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
Question


53
1) Do we need to CIP a vessel if we are going to transfer
the EXACT same solution in it again?
2) Why?
GMP Expectations
54

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.
GMP Expectations
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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.
Advantages of Automated CIP
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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
CIP Hazards
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57
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).
COP (Clean Out of Place)


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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.
COP - Small Vessel
59
COP - Bath
60
COP - Spool Piece
61
Question
Why not manually wash small parts?
62
COP - Hazards
Hazards 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
63
6) SIP (Steam In Place)
64
SIP Overview
 Automated steaming system
 Kills microorganisms and
spores
 Releases massive energy when
the saturated steam comes into
contact with the
microorganisms
65
SIP Operation
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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
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 )
67
SIP Key Functions
68

Air Removal

Condensate Removal
Air Removal
 Steam/ air mix will result in
unsaturated steam
(saturated steam required to
kill microorganisms)
 Performed by bleeds at high
points
69
Condensate Removal
70

Condensate also creates an
unsaturated steam condition

Condensate will cause cool
spots

Removed by low point Traps
Typical SIP Cycle
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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
SIP Hazards
72

High temperatures

Pressurised steam - can blow off
loose connections

Unlagged plant in high risk areas
SOP (Steam Out of Place)
73

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
SOP - Hazards
74

High temperatures

Pressurised steam - can blow
off loose connections

Potential for technicians to be
exposed to pressurised steam
SOP Recommendations
75

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
6) Autoclaves
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Autoclave
77
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
78
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
80
Process Description Cont.

Exposure
 Sterilisation

Post-conditioning
 Vacuum
Level & Hold and Pressure Level & Hold or
 Slow Exhaust
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Equalisation
7) (Parts) Washers
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Washer Function

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Designed to insure adequate cleaning, rinsing and
drying of product contact surfaces (e.g. Media/ Buffer/
Filling Line Parts)
Washer Process Overview

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84
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 oncethrough final rinse
Filtered, heated air is circulated through cabinet during drying
cycle
Washer Cycle
85
Washer Process Description
 Prewash
 Circulated
Detergent Wash
 2 x Circulated Rinse
 Non-circulated WFI Rinse
 Drying
86
Washer Process Description - Prewash
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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
Washer Process Description - Circulated
Detergent Wash
88

Hot WFI Sump fill

Detergent is dispensed to the washer for specified
amount of time (Must reach specified conductivity)

Circulation

Drain
Washer Process Description - 2 x
Circulated Rinse

As per Prewash

Temperature & Time setpoints variable
89
Washer Process Description Non-Circulated WFI Rinse
90

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
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
91
8) Solution Transfer
92
Transfer of Solutions
Having made up various solutions/ ingredients….. How
do you get a solution made in Tank A into Tank B?
93
Transfer of Solutions

Lines

Pumps

Pressure

Transfer panels

94
Let’s look at transfer panels in more depth
What is a Transfer Panel?
95
Transfer Panels
96

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
Transfer Panel & Jumpers
97
Jumpers
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Question - Transfer Panel Hazards
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What types of hazards can you think of that are
associated with transfer panels?
Question - Transfer Panel Hazards
When transferring solutions,
hazards can include:
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100
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
QUESTIONS???
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