Professional Documents
Culture Documents
1 Water
1 Water
II
III
IV
Microbiology of water
VI
Deionization / Electro-deionization
all groups.
USP has 9 chemistry tests for Sterile Water for
Injection (SWFI), after preparing WFI!
USP plans to reduce to 2 test
- Conductivity (same limits as EP?)
- Quantitative organic analysis test (TOC or
spectrophotometric)
EP has ~ 15 wet chemistry tests for SWFI,
plus conductivity
Pharmacopoeias
Regulatory Bodies
The Pharmacopoeia
requirement
USP 28
General Information
<6D dead legs
sloped piping lines
complete drain ability
no pockets
sample valves
sanitization
installation and materials of construction
Regulatory Bodies
European Medicines Evaluation Agency
(EMEA)
Agencies in member nations
e.g. Medicines Control Agency (MCA)
from April 1st 2003 Medicinal and
Healthcare products Regulatory Agency
(MHRA)
Food and Drug Administration (FDA)
Enforcement
Regulatory bodies legally enforce drug
standards
Safety
Efficacy
Strength
Purity
Enforcement (2)
Pharmacopoeias set drug standards but
cannot enforce them
MHRA/FDA enforce drug standards but
cannot set them
There are many grey areas open to
interpretation by different regulators
Process requirements
regulatory requirements
each process step
all critical parameters chemical,
physical and biological
Fabrication
Commissioning
Vendor testing
Field Inspection
USP 28
WFI Requirements
Source water defined
Distillation or RO
Conductivity 3 Stages
TOC 500 ppb
BET 0.25 EU/ml
Micro count 10 cfu/100 ml
(guideline <1231>)
USP 28
Purified Water Requirements
Source water defined
Suitable process
Conductivity 3 Stages
TOC 500 ppb
Micro Count 100 cfu/ml
(guideline <1231>)
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
0.6
0.8
0.9
1.0
1.1
1.3
1.4
1.5
1.7
1.8
1.9
2.1
2.2
2.4
2.5
2.7
2.7
2.7
2.7
2.9
3.1
If the conductivity is higher than the table value, proceed with Stage 2.
Stage 2
Transfer a sufficient amount of water (100 ml
or more) to a suitable container, and stir the test
specimen. Adjust the temperature, if necessary,
and while maintaining it at 25 10, begin
vigorously agitating the test specimen while
periodically observing the conductivity. When
the change in conductivity (due to uptake of
atmospheric carbon dioxide) is less than a net of
0.1 S/cm per 5 minutes, note the conductivity.
If the conductivity is greater than 2.1 S/cm,
proceed with Stage 3.
5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
6.0
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9
7..0
4.7
4.1
3.6
3.3
3.0
2.8
2.6
2.5
2.4
2.4
2.4
2.4
2.5
2.4
2.3
2.2
2.1
2.6
3.1
3.8
4.6
If either the measured conductivity is greater than this value or the pH is outside the range of
5.0 to 7.0, the water does not meet the requirements of the test for conductivity.
Conductivity
Agreed replacement for wet chemistry
Theory and model similar in US and Europe
Detailed application very different
EP differs for WFI and PW
No on-line provision in EP
Different temperatures
EP retains Nitrates
EP Conductivity
EP introduced conductivity in 1999 (2.2.38)
Difficulty complying, several anomalies
Not designed for on-line testing
States use platinum electrodes (not optimal)
Temperature compensation unclear
Lack appreciation of CO2 equilibrium
EP update expected
Uncompensated conductivity, si
10.0
9.0
8.0
7.0
6.0
5.0
Proposex1 EP WFI Limits
4.0
3.0
2.0
1.0
0
0
10
20
30
2.9 3.1
2.7
2.7
2.7
2.7
2.5
2.2 2.4
2.1
1.7 1.8 1.9
40
50
60
Temperature (oC)
70
80
90
100
TOC
TOC = Total Organic Carbon
Non-purgeable organic carbon
Replacement for Oxidisable Substances
Introduced USP 1996
Introduced EP 1999
Previously in JP
Microbiological Requirements
Water for Injection
USP 28
10 cfu/100 ml (<1231>)
0.25 EU/ml
Distillation or RO
EP 4th (2002)
Microbiological Requirements
Purified Water
USP 28
EP 4th (2002)
No
WFI
Downstream
Processing
Yes
PW
Sterile Products
No
PW
Parenteral
Product
Yes
WFI
Cleaning Water
Cleaning Water used for
No
Suitable
non compendial
water
Final
rinse
Yes
GMP Requirements
General
Provide guidance
Need to be applied according to local conditions
Used in conjunction with pharmacopoeial
requirements and registered details as basis for
inspection
Industry norm
continuous progression
USA GMP
21 CFR Part 210 Interpretation
Pharmaceutical waters used in the
manufacture of drugs or drug products
are subject to the regulations of the
cGMPs whether or not the water remains
in the final product
USA GMP
21CFR Part 211.48a
Potable water shall be supplied under
continuous positive pressure in a
plumbing system free of defects that
could contribute contamination to any
drug product. Potable water shall meet
the standards prescribed in the EPAs
Primary Drinking Water Regulations
USA GMP
21CFR Part 211.48b
Drains, where connected to a sewer,
shall be provided with an air break
Of particular concern on sanitisation
or product divert lines
Air breaks preferred to check valve or
backflow preventers
Common drains should be scrutinised
to ensure there is no possibility of
back contamination
USA GMP
21CFR Part 211.65a
Surfaces that contact components, in
process materials, or drug products shall
not be reactive, additive, or absorptive so
as to alter the safety, identity, strength,
quality, or purity of the drug product
USA GMP
21CFR 211.65b
Any substances required for
operation, such as lubricants or
coolants, shall not come into contact
with components so as to alter the
safety, identity, strength, quality, or
purity of the drug product beyond the
official or other established
requirement
USA GMP
21CFR 211.67b
Equipment shall be cleaned,
maintained, and sanitised at
appropriate intervals to prevent
malfunctions or contamination that
would alter the safety, identity,
strength, quality, or purity of the drug
product beyond the official or other
established requirement
USA GMP
21CFR 211.67b
Written procedures shall be
established and followed for cleaning
and maintenance of equipment
SOP required for operation and
maintenance of pharmaceutical water
systems
USA GMP
21CFR 211.67c
Records shall be kept of maintenance,
cleaning, sanitising, and inspection
Sanitisation, cleaning, and
maintenance procedures shall be
documented
Sanitisation and cleaning performance
shall be validated and records shall be
maintained
V. Microbiology Requirements
EP limits are ACTION LIMITS in Production section
- Purified Water100 cfu/ml
- WFI..10 cfu/100 ml
Alert Levels
Alert -
Constantly reviewed
Action Levels
Action - Exceeded indicate process has
drifting from normal operation
- Corrective action requiring
- Often based on Regulatory
Guidelines but should also take
account of local situation
Method
Frequency
Limit
Potable
Pour Plate
Membrane
3 Months
Absence of
specific
organisms
500 cfu/ml
Purified
Pour Plate
Membrane
Weekly (70%)
100 cfu/ml
WFI
Pour Plate
Membrane
Daily (90%)
10 cfu/100ml
Microbial Control
Capital Equipment Cost
Operating Cost
Lifecycle Cost
Chemical Handling
Reliability / Uptime
Maintenance
Water Consumption / Discharge
Footprint plantroom space
Consistent TOC Limit Attainment
Consistent Conductivity Attainment
Distillation
Preferred method of production for WFI
Purifies water by phase change and entrapment
separation
Removes :
ionic contaminants
non-volatile organics
microorganisms
endotoxins
Distillator
Reverse Osmosis
Pressure driven semi-permeable membrane
process
Implemented for reduction of :
Inorganic contaminants
Organic contaminants
Colloids
Microorganisms
Endotoxins
Reverse Osmosis
Performance measurement/determination
Salt rejection
Comparative conductivity (product to
feed)
Microbial reduction
Endotoxin reduction
Reverse Osmosis
Microbial concerns
Most systems cannot tolerate chlorine in
feed water at it tends to hydrolyse the
membranes
Significant bio-film and planktonic counts
can occur
Frequent sanitization is often required
Pretreatment system performance is
significant factor
RO Specification
Pretreatment and post-treatment
Feed filter housing (and elements)
Chemical tanks / pumps / controls
Cleaning skid (or sanitization skid)
RO Pretreatment Parameters
Feed water quality
Membrane type
Product water quality specifications
Materials of Construction
Comparison Factors
Corrosion resistance
Availability
Extractables
Degree of Thermal expansion
External support requirements
Joining method
Sanitization Options
Clean Steam
Extremely effective & verifiable
Requires full drainability & venting
Beat in SS
Possible in PVDF
Requires continuous support
Requires significant expansion loops
Limited to 1400C
Sanitization Options
Hot water
Very effective at 800C
Can be done under pressure >1000C
Best in SS
Easily verified
Easily automated
Sanitization Options
Ozone
Best in SS and PVDF (+PP)
Very effective if frequent enough
Easily automated if already continuous in
storage tank
Easily removed with UV
Verifiable with monitors
Difficult to sanitize through use point valves
Good at biofilm removal with time
Peracetic acid
Sodium hydroxide
Hydrogen peroxide
Quaternary ammonium compounds
Most difficult to verify
Most difficult to automate
Most difficult to rinse
Compatible with wide range of materials
Ozone
Microorganism kill faster than chlorine
Most bacteria killed in seconds
Lyses cell wall-not dependent on diffusion
through cell wall
Ozone
Capable of organic oxidation including
endotoxin
Ozone Removal
Dissolved
- Ultraviolet light (3germicidal dose)
- Activated carbon
- Heat
- Time
Gas
- Manganese dioxide catalytic device
- Heat
Ozone Measurement
Chemical testing
- Indigo tri- sulfonate solution
decolorization
- absorbance change of 600 nm light
- linear with ozone level
- preferred method
systems
have been successful
Regional trends are variable about
use of ozone
Ozone Issues
Removal prior to use
Product efficacy impacted by trace
levels?
Personnel Safety monitoring required
Piping Systems
Material
- Stainless Steel 316 L.
- Seemless or drawn tube may be used.
- Tube mill finished 2B internally + mechanically polished
as part of tube manufacturing process.
- Electropolish improves finish and surface corrosion
resistance.
Insulation
- Pipework insulated with chloride free materrials. In
process areas, Insulation needs to be hygienic finish
Drainability if required
- Valve configuration
- Slope
MATERIALS SELECTION S
Corrosion minimisation and resistance
Avoidance of leachates from contact
materials
Avoidance of the development and
adherennce of bio-films
Avoidance of adhesion and retention of
contaminants and cleaning/disinfecting
residues
Aesthetically appropriate appearance
Inspectability of surfaces
Ability to joint materials
304
0.08
316L
0.03
Chromium
18.5
17.0
Nickel
9.5
13.0
Molybdenum
2.25
Piping system
PEEK Poly-ether-etherketone
PVDF Polyvinylidenedifluoride
PFA Perfluoroalkoxy
PP
Polypropylene
ABS Acrylonitrile-butadiene styrene
PVC Polyvinyl chloride
- peek>20Xcost of PVC
- main value in Microelectronics
EXAMPLES OF APPROVED
CONTACT MATERIALS
Typical Ra
m
General Description
0
1
n/8
5.0
2D
2B
0.5
0.275
2A
0.088
3A
1.5
Ground Brush,
0.8
Mirror polish
SURFACE FINISH
THE EFFECT OF ELECTROPOLISHING
A highly reflective finish can be obtained with
an Ra Value < 0.02m
Starting surface is critical to quality achieved be
electropolishing. 2A or 2B cold rolled is
appropriate.
Used to be an essential specification in the dairy
industry. Now not so frequent as CIP Systems
and Chemicals improve.
Electropolishing diminishes the passive layer.
This must be restored to retain corrosion
resistance.
Installation QA Tasks
Materials certificated from supplier
Materials and equipment controlled at job site
Documented
Clean
In correct condition e.g. clean & dry
plant items.
Dispensed for installation.
Clean Installation protocol
Installation QA Tasks
Weld Log
Operator
Qualification
Checks/Certification
Equipment
Reference
Settings
Maintenance
Samples
Weld i/d
Installation QA Tasks
Installation Records
Specifications
Drawings
Components
Change control records
Installation QA Tasks
Inspection
Visual - Boroscope
Photograph
Samples
X-ray
Retained Samples
Validation User
Responsibility
Must follow an
approved protocol
Typically operated by
supplier
Validation
start-up/shut-down (normal/emergency)
sanitisation/cleaning
operation (including log)
sampling/testing
specific procedures
chemical addition, etc.
Validation Overview
System Design (pre-validation)
Installation Qualification
Operational Qualification
Performance Qualification
Change Control
Regular Review (Annual system review)
This presentation will not deal with all the
normal validation steps. BUT PQ is special for
water systems
(Installation Qualification for Purified Water)
1.
1.1 Non-Return (Foot Valve)
1.2 Lowara CA200/35 3 2
1.3 UPVC 1
1.4 Non-Return
1.5 Power Supply 3 PH/ 380 V/ 50 Hz
2. 200
2.1 1
2.2 1
2.3
2.4
2.5 100
3. Ametek 20 /30
2
3.1 3/4
3.2 3/4
4. 38x120 .
4.1 Multiport Autotrol 180/450
4.2 1
4.3 1
4.4
4.5 POWER SUPPLY 220 V
4.6 SAMPLING VALVE
5. S 37B
5.1 1
5.2 1
5.3 POWER SUPPLY 220 V
5.4 UV-MONITOR
-
-
7. RO. 3,000
7.1 1 /
7.2 1 /
7.3 Manhole 18
7.4 VENT FILTER
8. 4HMS5 0.75 Mixed Bed 2
8.1 1
8.2 1
8.3 POWER SUPPLY 1 PH / 220 V / 50 Hz
8.4 Non-Return Valve
9. 38x185 .
9.1 - 1
9.2 PLASTIC DIAPHRAGM VAVE 1 8 / 1/2 6
9.3 STAGER CONTROLLER 1
9.4 AIR COMPRESSOR 1
9.5 SIGHT GLASS 2
9.6 1
9.7 SAMPLING VALVE
9.8 NaOH 50% TANK (PE)
9.9 EJECTOR () NaOH
10. 20 / 5 1 / 1 1
10.1 1
10.2 1
11. LM-1
11.1 POWER SUPPLY 220 V 50 Hz
11.2 ELECTRODE SO-1 C=0.1
12. Sanitron S 50B
12.1 1 1/2
12.2 1 1/2
12.3 POWER SUPPLY 220 V
12.4 UV-MONITOR
-
-
13. 6,000
13.1 1 1/2 / 1 1/2
13.2 /
13.3 Solenoid Valve
13.4 Manhole 18
13.5 VENT FILTER
14. 2 INOXPA EFI 2340
14.1 1 1/2 (Sanitary Type)
14.2 1 (Sanitary Yype)
14.3 Non-Return Valve
14.4 POWER SUPPLY 3 Phase/380 V/50 Hz
14.5
(1.1) 2 1
40 80 PSI
30 (1.2)
Activated Carbon (1.3)
- Backwash
- Backwash
5. (1.4)
..
..
..
..
..
..
..
..
..
..
- Conductivity
20
- Concentrate
- Solenoid UV (1.4)
RO
..
..
..
..
..
..
..
..
..
....
..
..
..
..
..
..
..
..
..
..
..
Pressure Tank
(1.1) ()
Activated Carbon
RO Pre-Filter (1.2)
Filter RO RO
Pre-Filter Membrane
Flow (L/Hr)
Product
Concentrate
Circulate
Conductivity
(Microsiemens)
................
Conductivity ()/0C
(CFU/ml)
TOC (ppb)
O3 (ppm)
pH value
(Installation Qualification for Water for Injection)
1. 500
1.1
1.2 FEED GRUNFOS CRN2-70
1.3
1.4 SENSOR
1.4.1 SENSOR , CONDUCTIVITY Loop 1
1.4.2 SENSOR 1
1.4.3 SENSOR , CONDUCTIVITY Loop 2
1.4.4 SENSOR 2
1.4.5 LEVEL SENSOR 1
1.4.6 LEVEL SENSOR 2
1.4.7 DI (1.12)
1.5 CONTROL PANEL
1.6
2. 4,000 (2.4)
2.1 6 KW 2
2.2 2 HP /3 PHASE
2.3 VENT FILTER
2.4 LEVEL PROBE
2.5 CIRCULATE
1 Self drain Dead leg Diaphragm
3. 1,500
3.1 6 KW 1
3.2 2 HP/3 PHASE
3.3 VENT FILTER
3.4 LEVEL PROBE
3.5 CIRCULATE
1 Self drain Dead leg Diaphragm
4. COOLING TOWER 40
4.1 1
4.2 380 V/50 Hz
4.3 PUMP CIRCULATE COOLING 380 V / 50 Hz
4.4 CIRCULATE COOLING
CONDENSOR BY-PASS VALVE
5. DRAIN ,
6. STEAM BOILER
6.1 FEED
6.2 FEED Anti-Corrosion
6.3 500 Kg / Hr
6.3.1 3
6.3.2 VENT VALVE
6.3.3 SAFETY VALVE
6.3.4 DRAIN
6.3.5 PRESSURE GAUGE 200 PSI
6.4 HEADER
6.4.1 SAFETY VALVE
6.4.2 PRESSURE GAUGE 200 PSI
6.4.3 STEAM TRAP
6.5 500
6.5.1
6.6
6.7 380 V / 50 Hz / 3 PH
7. STEAM
.
.
.
.
.
.
.
.
.
- Probe Loop 1
- Probe Loop 2
- Probe Conductivity
Loop 1
- Probe Conductivity
Loop 2
- Probe Loop 1
- Probe Loop 2
- Heated Vent (2.4)
- Filter 100-120
- Heated Vent (2.7)
- Filter 100-110
- Test Heater (2.4)
.
.
.
.
.
.
.
.
.
.
.
................................
Conductivity < 1
100 CFU/ml
TOC (ppb) at0C
SIP ....................
. ...............
Conductivity ()
(CFU/ml)
TOC (ppb)
pH value
Performance Qualification
Activity expected by Regulator (but perform
for Company!)
Documented verification of proper system
operation in meeting predetermined
acceptance criteria
Follows IQ and OQ execution and resolution
of all critical deviations
Revalidation
Appropriate for major system changes
Determined via change control process
Periodic revalidation is not required
Perform regular review
V-Model
User Requirement
(i.e. What)
Functional Design
(i.e. How as Schematic)
PQ Test Plan
OQ Test Plan
Performance
Qualification
Operational
Qualification
Design
Development
Detail Design
(i.e. How to make)
IQ Test
Impact Assessment
Implementation
Installation
Qualification
Troubleshooting
Follow plan, avoid panic or short cuts
How it works
Normal parameters
Sensitivity to change
Maintenance requirements
Troubleshooting Procedure
Methodical, no panic
Collect evidence
samples
Instrument readings
Importance of Monitoring
Maintain product quality
Maintain equipment
Protect investment
Detect changes in incoming water
Maximise run time
Minimise service time
Historical tracking
Stringent Change Control
Change in supply
Sudden variations
Temperature
Seasonal
Adverse weather (floods, drought)
Chemical attributes
Microbiological profile
Endotoxin content
Volume produced
1)
400C
2) PRESSIRE GAUGE
() PRESSURE GAUGE
30-60 PSI () DRAIN
()
3)
6
4) ACTIVATED CARBON
(BACK WASH)
5) UV-MONITOR
0.4-10 () 0.4 ()
UV
QUARZT (WIPER) 2-3 DRAIN
DRAIN
6) REVERSE OSMOSIS PLC
AUTO FLUSHING FLUSH CONDU CTIVITY
FLUSH FLOW METER PRESSURE GAUGE
8) -
- -
-
- Carbon Filter
- Ozone, Conductivity DI
Anti-Scale Anti-Scale RO
- UV
References:
1) FDA,Guide to inspection of High Purity Water System July 1993
2) ISPE Baseline Pharmaceutical Engineering Guide, and Water and
Steam System
3) ISPE Baseline Pharmaceutical Water System
4) USP 28: 2005
5) BP 2002 ,Volume 1 and 2
6) Ph.Eur 4th,Edition
7) Gordon Farquharson: Pharmaceutical Grade Water Basis
8) Robert Chew : Commissioning and Qualification of Water
9) Antony Margetts: Validation Concept