TOT Water For Pharmaceutical Use - Part 1

Water for Pharmaceutical Use
WHO Technical Report Series

No 970, 2012. Annex 2
Water
Slide 1 of 25
2013
Supplementary Training Modules on

Good Manufacturing Practice
GMP Principle & Target AVOIDING
MIX UP & CROSS CONTAMINATION
GMP Approach
Systematic & SCIENTIFIC WAY &
RISK ASSESMENT with Patient Safety
Main Orientation
Water
Slide 2 of 25
2013

Objective
General principles, water system requirements and uses
Water quality specifications
Application of specific types of water to processes and dosage
forms
Water purification systems, storage and distribution
Operational considerations
Inspection of water systems
Water
Slide 3 of 25
2013

Introduction
Look at information on specifications of Water for
Pharmaceutical Use (WPU)
Which Quality of water to be used in production and control
APIs, finished products, etc.
GMP for design, installation, operation of systems

Supplementary to general GMP guidelines
See also other guidelines, pharmacopoeia, etc.
Water
Slide 4 of 25
2013
1.1.1 1.1.2

Additional guidelines
WHO Guideline for Drinking water quality (WHO)
Water and steam systems (ISPE)
Bioprocessing Equipment Standard (ASME BPE 2000)
European Pharmacopoeia, United States Pharmacopeia,
International Pharmacopoeia
Inspection of Utilities (PIC/S)
1.1.3
Water
Slide 5 of 25
2013

Principles
Like any starting material, production of water should conform to
Good Manufacturing Practice (GMP) norms
Potential for microbial growth
Systems must be properly validated / qualified
Water for parenteral use should not be contaminated with
pyrogens or endotoxins
Specifications and periodic sampling and testing required
Water
Slide 6 of 25
2013

Why purify raw water?
Although reasonably pure, it is always variable due to
seasonal variations, regional variation in water quality
Must remove impurities and control microbes to avoid
contaminating products
Treatment depends on waters chemistry and
contaminants, influenced by, e.g. rainfall, erosion,
pollution, dissolution, sedimentation, decomposition
Water
Slide 7 of 25
2013

Contaminants of water (1)
There is no pure water in nature, as it can contain up to 90
possible unacceptable contaminants
Contaminant groups:
Inorganic compounds
Organic compounds
Solids
Gases
Microorganisms
Water
Slide 8 of 25
2013

Problem minerals
Calcium, magnesium, copper, aluminium, heavy metals,
arsenic, lead, cadmium, nitrates
Iron, manganese, silicates, carbon dioxide
Hydrogen sulfide
Phosphates
Water
Slide 9 of 25
2013

Microorganisms Biofilm formation
Protozoa
Cryptosporidium
Giardia
Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms
Water
Slide 10 of 25
2013

Biofilm formation
1. Free-swimming aquatic bacteria use polymucosaccharides to
colonize surfaces
2. Complex communities evolve which shed
microcolonies and bacteria
Water
Slide 11 of 25
2013

Background to water requirements and use
Water is the most widely used substance / raw material
Used in production, processing, formulation, cleaning, quality
control
Unique chemical properties
Able to dissolve, absorb, adsorb, suspend compounds and
contaminants
Different grades of water quality available
See also EMEA "Note for guidance on the quality of water for
pharmaceutical use"
1.2.1
Water
Slide 12 of 25
2013

Background to water requirements and use (2)
Control quality of water during production, storage and
distribution
Contaminants, microbial and chemical quality

Microbial contamination risk and concern
Water is used on demand
not like other materials where sampled and tested, and THEN
used. Thus no batch or lot release before use. It has to meet the
specification "on demand" when used
1.2.2
Micro test results require incubation periods therefore results later

after already used
Water
Slide 13 of 25
2013

Background to water requirements and use (2)
Microbial control is a high priority
Microbes may proliferate (production, storage and
distribution)
System design, periodic sanitization and other
measures
Different grades of water quality (dependent
on its use)
1.2.3. 1.2.4.
Water
Slide 14 of 25
2013

General Principles of water systems
Design, installation, commissioning, qualification /
validation, operation, performance and maintenance to
ensure reliable, consistent production of water of required
quality
Prevent unacceptable microbial, chemical and physical
contamination during production, storage and distribution
Operate within design capacity
Quality Assurance involved in approval of use after
installation and maintenance work, or changes
Water
Slide 15 of 25
2013
2.1. 2.3.

Water system requirements (2)
Regular monitoring of:
Water quality
Chemical and microbiological
Endotoxin level where relevant
System performance, storage and distribution systems

Records of results, trends and action taken
Validated sanitization procedure followed on a routine basis
2.4. 2.5.
Water
Slide 16 of 25
2013

Presentation of water processed, stored and distributed in
bulk. (Not applicable for patient administration)
Specifications in pharmacopoeia include different types of
water
Drinking water / potable water
Bulk Purified water (BPW)
Bulk Highly Purified Water (BHPW)
Bulk Water for Injection (BWFI)
Water
Slide 17 of 25
2013
3.

Drinking water / potable water
Must comply with specification (WHO, ISO and national or
regional agencies) regular testing needed
Supplied under continuous positive pressure
Defect free plumbing system to prevent contamination
Could be from public water supply system or natural
sources
Source water quality influences the treatment required
3.2.1., 3.2.3.,
3.2.6.
Water
Slide 18 of 25
2013

Drinking water:
Natural sources could include
springs, wells, rivers and lakes
Treatment includes
desalinization, softening, removal
of specific ions, particle reduction
and antimicrobial treatment.
3.2.2
Water
Slide 19 of 25
2013

Bulk Purified Water (BPW)
Prepared from potable water (as minimum quality feed)
Meet pharmacopoeia specification - chemical and microbial
purity
Alert and action limits (determined)
Protected from recontamination
Protected from microbial proliferation
RO/EDI
Water
Slide 20 of 25
3.3.1.
2013

Bulk Highly Purified Water (BHPW)
Prepared from potable water (as minimum feed)
Specification only in the European Pharmacopoeia
Same quality standard as WFI (microbiological and limit for
endotoxins)
Prepared by combination of methods including double
reverse osmosis (RO) plus ultrafiltration (UF) and
deionization (DI)
Protect from recontamination and microbial proliferation
3.4.1. 3.4.3.
Water
Slide 21 of 25
2013

Bulk Water for Injections (BWFI)
Prepared from potable water source treated further, or PW
WFI is not sterile and is not a final dosage form
WFI is an intermediate bulk product
According to The International and European
Pharmacopoeias final purification step should be distillation
To meet pharmacopoeia specification for chemical and
microbial purity (including endotoxin)
Alert and action limits
Water
Slide 22 of 25
2013
3.5.1 3.5.4.

Application of specific types of water to
processes and dosage forms
Water used for different stages of:
Washing, preparation, synthesis, manufacturing, formulation
Which grade of water is suitable for a particular stage?

As required by national authority
Consider nature and intended use of intermediate or finished product
Stage in process where water is used
Let's look at types of water and indicate their use

4.1. 4.2.
Water
Slide 23 of 25
2013

Application of specific types of water to
processes and dosage forms
BHPW
preparation of products when water of high quality (i.e. very low in
microorganisms and endotoxins) is needed
BWFI
manufacture of injectable products for dissolving or diluting substances or
preparations during the manufacturing of parenterals
manufacture of sterile water for preparation of injections
final rinse after cleaning of equipment and components
preparation of steam
4.3. 4.5.
Water
Slide 24 of 25
2013

Complete the table
Use
Which type of water?
Preparation of injectable products
Final rinse of equipment after

cleaning
Final rinse of equipment and

components that come into
contact with injectable products
Water
Slide 25 of 25
HPW
Potable water
2013

Water purification systems: So far:
Principles for pharmaceutical water systems
Drinking-water, Bulk purified water, Bulk highly purified water, Bulk water for
injections
Specific types of water for processes and dosage forms

General considerations for water purification systems
Next slides focus on water purification, storage and distribution
systems
Water
Slide 26 of 25
2013

Water for
Pharmaceutical
Use
No 970, 2012. Annex 2
Part 2
Water purification,
storage and
distribution
Water
Slide 27 of 25
2013

Objectives
To examine the basic technology and
requirements for:
Water purification systems
Storage and distribution requirements
Sanitization
5. - 6.
Water
Slide 28 of 25
2013

Manufacturer to select appropriate method of purification
Appropriate sequence of purification steps
Influenced by, e.g.
Water quality specification
Feed water quality
Reliability and robustness of treatment system
Supplier support, maintenance and operation costs
5.1.1 5.1.2.
Water
Slide 29 of 25
2013

Water purification systems (2)
Influenced by, e.g.
the final water quality specification
the quantity of water required by the user
the available feed-water quality and the variation over time
(seasonal changes)
the availability of suitable support facilities for system
connection (raw water, electricity, heating steam, chilled water,
compressed air, sewage system, exhaust air)
5.1.1 5.1.2.
Water
Slide 30 of 25
2013

Water purification systems (3)
Influenced by, e.g. (cont.)
sanitization method
the reliability and robustness of the water-treatment equipment in
operation
the yield or efficiency of the purification system
the ability to adequately support and maintain the water
purification equipment
the continuity of operational usage considering hours/days, days/
years and planned downtime
5.1.1 5.1.2.
the total life-cycle costs
Water
Slide 31 of 25
2013

Water purification system considerations:
Location of the plant room; temperatures
Leachates and adsorptive contact materials
Hygienic or sanitary design
Corrosion; leakage
Proliferation of microbiological organisms, cleaning; sanitizing
Capacity and output requirements
Instruments, test and sampling points
Water
Slide 32 of 25
2013
5.1.3

Water purification system considerations (2)
Physical considerations:
Ability to collect samples
Space available for the installation
Structural loadings on buildings
Adequate access for maintenance
Regeneration and sanitization chemicals.
5.1.4
Water
Slide 33 of 25
2013

Pre-treatment steps
Primary filtration and multimedia filter
Coagulation or flocculation
Desalination
Softening
Water
Slide 34 of 25
2013

Pretreatment
schematic
drawing
float
operated
valve
excess water recycled

from deioniser
air filter
sand filter
spray ball
Water is kept
circulating
raw water in
centrifugal pump
S trap to sewer
|
Slide 35 of 25
2013
To water
softener &
DI plant
break tank
air break to drain
Water
activated
carbon
filter
cartridge
filter
5 micrometers

Water pre-treatment
complex in a pretreatment room
Water
Slide 36 of 25
2013

Water Softener schematic drawing
by pass valve
"soft" water to deioniser
brine and salt tank
brine
"hard" water
in
drain
Water
Slide 37 of 25
2013
zeolite water softener

-exchanges
-Ca and Mg for Na

Chlorine removal (Activated-carbon (AC)
filtration or bisulphite)
AC removes chlorine but bacteria can then grow
AC filtration can remove organic impurities
Bisulphite leaves sulphate residues but is antimicrobial
Water
Slide 38 of 25
2013

Production of drinking water
Derived from raw water source (e.g. well, river, reservoir)
Processes may include:
desalinization; filtration
softening; disinfection or sanitization (e.g. by sodium hypochlorite
(chlorine) injection)
iron (ferrous) removal
precipitation
reduction of concentration of specific inorganic and/or organic
materials
5.2.1 5.1.2.
Water
Slide 39 of 25
2013

Drinking water (2)
Routine monitoring of quality cover environmental, seasonal or
supply changes
Additional testing when change in the raw water source,
treatment techniques or system configuration
Trend review
When quality changes significantly, but is still within specification, the direct
use as a WPU, or as the feed-water to downstream treatment stages,
should be reviewed and the result of the review documented
5.2.3. 5.2.5.
Water
Slide 40 of 25
2013

Drinking water (3)
Producing drinking water through an "in-house" system
requires well documented system configuration and water
quality monitoring
Change control approved by QA
Storage of water:
no degradation, ensure turnover, routine testing
"indirect impact system" qualification not needed
Water
Slide 41 of 25
2013
5.2.6. 5.2.8.

Drinking water (4)
System design allows for draining and sanitization
Closed storage tanks:
With protected vents
Allows for visual inspection
Draining and sanitization possible (also pipework)
Control microbiological contamination of sand filters, carbon

beds, water softeners. Measures include:
5.2.10. 5.2.11.
back-flushing, chemical or thermal sanitization and frequent
regeneration, continuous waterflow
Water
Slide 42 of 25
2013

Drinking water (5)
When supplied in bulk or by tanker identify problems and
risks
Risk control:
Vendor assessment
Authorized certification activities
Acceptability of delivery vehicle
Similar as other starting materials

5.2.9.
Water
Slide 43 of 25
2013

Production of Purified Water (PW) (1)
Slide 44 of 25
2013
raw water
drain or recycle
Purified water
Permeate
water
Water
under
pressure
Reject
water
Includes: Ion exchange,

Reverse Osmosis,
Ultrafiltration and/or
EDI and distillation
Feed
water
Semi-permeable
membrane
Use appropriate, qualified

methods to produce PW.
Low pressure
High pressure
5.3.1.

Factors to consider in URS for PW:
feed-water quality (and variation over seasons) and waterquality specification;
quantity of water required;
sequence of purification stages and energy consumption;
extent of pretreatment needed;
performance optimization;
appropriately located sampling points;
appropriate instrumentation to measure parameters such as
flow, pressure, temperature, conductivity, pH and total organic
carbon.
5.3.2.
Water
Slide 45 of 25
2013

Production of Purified Water (2)
Ambient temperature PW systems are susceptible to
microbiological contamination especially when static and
periods of low or no demand
Evidence of effective controls
Sanitization at different stages of purification
If agents are used proof of removal
5.3.3
Water
Slide 46 of 25
2013

Production of Purified Water (3)
Controls may include:
Maintain minimum flow at all times
Control temperature in the system e.g. < 25 C
Provide ultraviolet disinfection
Use components that can periodically be thermally sanitized
Chemical sanitization (e.g. ozone, hydrogen peroxide and/or
peracetic acid) and thermal sanitization at > 70 C
5.3.4.
Water
Slide 47 of 25
2013

Production of Highly Purified Water (HPW)
Produced by double-pass reverse osmosis coupled with
ultrafiltration or by any other appropriate qualified purification
technique or sequence of techniques.
Same principles as for Purified Water
5.4.1. 5.4.2
Water
Slide 48 of 25
2013

Typical 2-stage RO schematic
Water from softener or de-ioniser
Second stage reject water goes back to first stage buffer tank
1st stage reject concentrate
1st stage buffer tank
First stage RO cartridge
Branch
Branch
First stage filtrate feeds second stage RO

. excess back to 1st stage buffer tank
with
Air break
to sewer
2nd stage buffer tank
Second stage RO cartridge
High pressure
pump
Second stage RO water
meets Pharmacopoeia
standards
Water
Slide 49 of 25
2013
Cartridge
filter 1 m
Hygienic pump
Water returns to 1st stage buffer tank

Outlets or storage

Production of Water for Injections (WFI)
Distillation is preferred technique also in some Pharmacopoeia
Factors to consider in design:
Feed water quality
Required water quality specification and quantity of water
Optimum generator (size and variable control to prevent
frequent start/stop)
Blow-down and dump functions
Cool-down venting (to avoid contamination ingress)
Similar principles as for PW
Water
Slide 50 of 25
2013
5.5.1. 5.5.3

Water storage and distribution systems
This section applies to WPU systems for PW,
BHPW and BWFI
The water storage and distribution to work in
conjunction with the purification plant to ensure
delivery of water of consistent quality to the user
points, and to ensure optimum operation of the
water purification equipment
6
Water
Slide 51 of 25
2013
What are the

main
components
in a water
storage and
distribution
?system
6.
Water
Slide 52 of 25
2013

Typical water storage and distribution schematic
Hydrophobic air filter
& burst disc
Feed Water
from
DI or RO
Cartridge
filter 1 m
Water must
be kept
circulating
Spray ball
Optional
in-line filter
0,2 m
UV light
Outlets
Heat Exchanger
Ozone Generator
Water
Slide 53 of 25
2013
Hygienic pump
Air break
to drain

General
PW usually stored in a vessel for subsequent use
Storage and distribution system is a key part of the whole system
Should be appropriately designed
Configured to prevent microbial proliferation and recontamination of
the water (PW, BHPW, BWFI) after treatment
Online and offline monitoring to ensure that the appropriate water
specification is maintained
6.1.1. 6.1.3
Water
Slide 54 of 25
2013

Contact materials
Materials that come into contact with WPU should
be appropriate
Includes:
Water
pipework
valves and fittings
seals
diaphragms and
Instruments
Slide 55 of 25
2013
6.2.1. 6.2.2.

Contact materials Considerations (1)
Compatibility
Prevention of leaching
Corrosion resistance
Smooth internal finishing
Jointing
Unions and valves
Water
Slide 56 of 25
2013
6.2.2.

Compatibility
Temperature and chemicals, operation, rest and sanitization
Prevention of leaching
Non leaching operation and sanitization
Corrosion resistance
SS316L, cleaning and passivation
Smooth internal finishing

Water
Slide 57 of 25
2013
6.2

Jointing
Smooth. Controls (welder qualification, set-up, work session
test pieces, logs, visual inspection reports
Unions and valves

Sanitary design (no threads)
Materials
E.g. SS316L, polypropylene, PVDF
Water
Slide 58 of 25
2013
6.2

System sanitization and bioburden control
Systems in place to control proliferation of microbes
Techniques for sanitizing or sterilization
Consideration already during design stage suitable
materials of construction.
Validated procedure
Special precautions if water not kept > 65 degrees Celsius
6.3.1. -.6.3.2.
Water
Slide 59 of 25
2013

Storage Vessel requirements
Design and size important
Capacity
Buffer capacity (generation and use); operate continuously,
avoid inefficiencies due to frequent on and off cycles
Sufficient for short-term reserve in case of failure
Contamination control consideration
Headspace (kept wet with spray ball / distributor device)
Nozzles (no dead zone design)
6.4.3
Vent filters (type, testing, use of heat)
Pressure relief valves and burst discs (sanitary design)
Water
Slide 60 of 25
2013
Storage Vessel
Considerations
and
components
Water
Slide 61 of 25
2013

Requirements for water distribution pipework
General considerations
Temperature control
Circulation pumps
Biocontamination control techniques
6.5.
Water
Slide 62 of 25
2013

General considerations
Continuous circulating loop
Control proliferation of contaminants
No filters in loops or at user points
Circulation pumps sanitary design
Stand by no stagnant water
6.5.1.1. 6.5.1.2.; 6.5.3.
Water
Slide 63 of 25
2013

Temperature control
Heat exchangers should not be source of
contamination
Double tube plate or double plate and frame or tube and shell
configuration preferred
arranged in continually circulating loops or sub-loops to avoid
static water
Where cooling is done for minimum periods of time
6.5.2.1. 6.5.2.3., 6.5.3

Water
Slide 64 of 25
2013

Biocontamination control techniques
Sanitization (chemical or thermal) - production
and distribution and include:
Continuous turbulent flow circulation
Shortest possible length of pipework
Isolated from adjacent hot pipes
6.5.4..2
Water
Slide 65 of 25
2013

Biocontamination control techniques (2)
Minimized deadlegs
(NMT 3D)
Pressure gauges separated

by membranes
Use of diaphragm valves
Sloped and fully drainable
Water
Slide 66 of 25
2013
6.5.4.2
Water
Slide 67 of 25
2013

What type of valves
?are these
Water
Slide 68 of 25
2013

Biocontamination control techniques (2)
There should be no dead legs
D
Flow direction arrows
on pipes are important
Dead leg:
Measured from the ID pipe
wall to centre line of the
point-of-use valve where
significant stagnation
potential exists
Water
Slide 69 of 25
2013
Dead leg section
Sanitary Valve
Water scours dead leg

The growth of microorganisms can be inhibited by:
UV radiation
Maintain system <25C or > 65C
Periodic and routine sanitizing of the system e.g.
with:
water > 70 C)
superheated hot water or clean steam
chemicals e.g. ozone
Water
Slide 70 of 25
2013
6.5.4.2.

Water for
Pharmaceutical
Use
Part 3:
Operational
considerations
No 970, 2012. Annex 2
Water
Slide 71 of 25
2013

Objective of this part is to discuss the
operational considerations of water systems
including:
Start up and commissioning
Qualification and validation
Continuous system monitoring
Maintenance
Water system review
Water
Slide 72 of 25
2013
7.

Commissioning
Planned, well defined, well documented commissioning can
help to ensure appropriate qualification and validation
Includes
setting to work and system set-up
controls and loop tuning
System performance parameters
If commissioning is part of qualification then appropriate

7.1
level of documentation and compliance with VMP
Water
Slide 73 of 25
2013

Qualification
WPU, BPW, BHPW, BWFI are "direct impact, quality critical
systems
Should be qualified and be subjected to DQ, IQ, OQ, PQ
DQ: Design review influenced by source water and required
water quality
IQ: Installation verification of the system
OQ: operational qualification
Water
Slide 74 of 25
2013
7.2

Qualification (2)
This presentation will focus on PQ
PQ demonstrates consistent and reliable performance of the
system
Three phase approach - over extended period

Proves reliability and robustness
Include tests on source water (drinking water quality)
7.2
Water
Slide 75 of 25
2013

Phase 1.
Daily sampling (or continuously monitor) of incoming feed-water
Cover two weeks of intensive monitoring
System should operate continuously without failure or
performance deviation
Water is not used for finished pharmaceutical product (FPP)
manufacturing during this period
7.2
Water
Slide 76 of 25
2013

The testing approach in Phase I:
Chemical and microbiological testing follow a defined plan
Include incoming feed-water daily to verify its quality
After each step in the purification process
Each point of use and at other defined sample points
Develop appropriate operating ranges
Develop and finalize operating, cleaning, sanitizing and
maintenance procedures
Water
Slide 77 of 25
2013
7.2

The testing approach in Phase I:
Demonstrate product water of the required quality and quantity
Use and refine SOPs (operation, maintenance, sanitization and
troubleshooting)
Verify provisional alert levels
Develop and refine test-failure procedure
7.2
Water
Slide 78 of 25
2013

Phase 2.
Follows Phase 1 further two week test period with intensive
monitoring using refined SOPs
Sampling scheme generally the same as in phase 1
May use water if commissioning and Phase 1 data okay
Phase 2 to show:
consistent operation within established ranges;
consistent production and delivery of water of the required

quantity and quality when the system is operated in accordance
7.2
with the SOPs
Water
Slide 79 of 25
2013

Phase 3.
Normally over one year after the satisfactory completion of phase 2
Water can be used for FFP manufacturing
Objectives of phase 3 include
to demonstrate reliable performance over an extended period
to ensure that seasonal variations are evaluated
The sample locations, sampling frequencies and tests should be

reduced to the normal routine pattern based on established
procedures proven during phases 1 and 2
7.2
Water
Slide 80 of 25
2013

Continuous system monitoring
After completion of phase 3 do a system review
Then implement a routine monitoring plan (based on results from
phase 3)
A combination of on-line monitoring and off-line sample testing
with qualified alarm systems
Verify that the water met the pharmacopoeia and in house
specification
7.3.1. 7.3.2.
Water
Slide 81 of 25
2013

Continuous system monitoring (2)
Parameters to be monitored include:
flow, pressure, temperature, conductivity and total organic carbon,
physical, chemical and microbiological attributes
Offline samples taken from points of use or dedicated sample

points (where points of use cannot be sampled)
Water samples to be taken in the same way as when water is
taken for use in production. (A suitable flushing and drainage
procedure followed)
Data analysed for trends RCA and CAPA
Water
Slide 82 of 25
2013
7.3.1. 7.3.3.

Maintenance
A controlled, documented maintenance programme covering:
Defined frequency for system elements; a calibration programme
SOPs for tasks; control of approved spares
Maintenance plan and instructions
Review and approval of systems for use upon completion of work
Record and review of problems and faults during maintenance
7.4
Water
Slide 83 of 25
2013

System reviews
Regular intervals by a team (from engineering, QA, microbiology,
operations and maintenance) and cover:
Water
changes made since the last review

system performance
reliability
quality trends
failure events
investigations
out-of-specifications results from monitoring
changes to the installation
updated installation documentation
log books and status of the current SOP list
Slide 84 of 25
2013
7.5.1.

System reviews (2)
For new / instable / unreliable systems, also review:
The need for investigation
Corrective actions and preventative actions (CAPA)
Qualification (DQ, factory acceptance test (FAT), IQ, site
acceptance test (SAT), OQ, PQ) or equivalent verification
documents
The monitoring phases of the system
7.5.2.
Water
Slide 85 of 25
2013

Summary
In Parts 1, 2 and 3 we looked at:
Water requirements and uses
general principles for pharmaceutical water systems
water quality specifications
application of specific types of water to processes and dosage forms

Water storage and distribution systems
Operational considerations
In Part 4 discuss approaches to inspection of water systems

Water
Slide 86 of 25
2013

Part 4:
Inspection of water
purification systems
No 970, 2012. Annex 2
Water
Slide 87 of 25
2013

I start with:
As much as I learn, as
much as I dont know
Water
Slide 88 of 25
2013

The Angle point of This Training session :
cGMP Compliance, QA &

Inspector Perspective for Water
System
instead of Technical Construction
perspective
Water
Slide 89 of 25
2013

GMP Principle & Target AVOIDING
MIX UP & CROSS CONTAMINATION
GMP Approach
Systematic & SCIENTIFIC Based &
RISK ASSESMENT with Patient Safety
Main Orientation
Water
Slide 90 of 25
2013

Chapter 4
Pretreatment
Options
Chapter 1
Introducti
on
Water
Chapter 2
Key Design
Philosophi
es
Slide 91 of 25
2013
Chapter 3
Water
Options and
System
Planning
Chapter 5
Final
Treatment
Options: NonCompendial &
Compendial
Purified
Water
Chapter 6
Final
Treatment
Options:
Water For
Injection
(WFI) 7
Chapter
Pharmaceutic
al Steam
Chapter 8
Storage and
Distribution
Systems
Chapter 9
Instrumentati
on & Control
Chapter 10
Commissionin
g and
Qualification
Chapter 11
Appendix
Key Design & Philosophies

Introduction
To understand:
The nature of producing pharmaceutical water is to minimize or
eliminate potential source of contamination
It must be demontrated tahat all pharmaceutical waters (noncompendial US Pharmacopeia (USP) monograph compendial
waters) can be produced consistenly to spesification
USP covers 2 compedial water qualities (USP PW and USP
WFI) and non compendial water
Water
Slide 92 of 25
2013
Key Design & Philosophies

Introduction
To understand:
The nature of producing pharmaceutical water is to minimize or
eliminate potential source of contamination
It must be demontrated tahat all pharmaceutical waters (noncompendial US Pharmacopeia (USP) monograph compendial
waters) can be produced consistenly to spesification
USP covers 2 compedial water qualities (USP PW and USP
WFI) and non compendial water
Water
Slide 93 of 25
2013

CPP
To understand:
Critical parameters are defined as those parameters that directly affect the
product Quality.
Ex: since microbial quality cannot be diretly monitored in real time, the
parameters relied upon to control microbial growth are normally considered
as CRITICAL. These may include temp, UV intensity, ozone concentration,
circulating system under positive pressure, etc. The rest compendial water
properties mandated in the official monograph obviously constitute critical
parameters
Water system inspection techniques and approaches
Water
Slide 94 of 25
2013
Water
Slide 95 of 25
2013

Objectives
To understand:
The specific requirements when inspecting water systems,
including associated documentation
Water system inspection techniques and approaches
Water
Slide 96 of 25
2013

Prepare an aide-memoire for items to inspect (1)
May include:
Schematic drawing review
Changes to system since installation
Sampling procedure and plan
Specifications, results and trends
Out-of-specification results
Annual system review
Deviations
Water
Slide 97 of 25
8.
2013

Prepare an aide-memoire for items to inspect (2)
Results of system performance monitoring
Out of limit results, failure investigations and alarms recorded
Sanitization procedures and records
Maintenance and repairs logs/records
Instrument calibration and standardization
Qualification and validation including DQ, IQ, OQ, PQ
Requalification when appropriate, etc.
8.
Water
Slide 98 of 25
2013

Where to start:
What is the water to be used for?
sterile products
non-sterile products, e.g. oral liquid products, external
applications
solid dosage forms
washing and rinsing
Start: Document review site verification followed by additional
document review
Water
Slide 99 of 25
2013

Verification:
Start with document review (e.g. schematic drawing of the
system, "water quality manual" if available, system review)
Review qualification reports, then change controls (in case of
changes and requalification if appropriate)
Do on site verification (system in accordance with the drawings,
no leaks, calibration etc.)
Start with source water supply
Then pre-treatment and treatment systems
Water
Slide 100 of 25
2013

Documentation should reflect information on: (1)
Pipeline
Valves (non-return type)
Breather points
Couplings
Pipe slope
Velocities
Sampling points
Drain points
Instrumentation
Flow rates
Water
Slide 101 of 25
2013

Documentation should reflect information on: (2)
Specification for each system element
Standard procedures for use
System changes
Routine and non-routine maintenance
Investigations and corrective action
Validation studies
Chemical and microbiological specifications
Sampling instructions
Test procedures
Responsible persons
Training requirements
Water
Slide 102 of 25
2013

On site review and verification for raw water
Storage may be required prior to pre-treatment
Check material of construction of tank
Concrete, steel are acceptable but check corrosion
Plastics or plastic linings may leach
Check the suitability of the cover

To keep out insects, birds and animals
Check disinfection practices
Water
Slide 103 of 25
2013

On site review and verification (e.g. PW):
Start with source water supply follow whole system "loop"
Walk through the system, verifying the parts of the system
as indicated in the drawing
Review SOPs "on site" with the relevant records, logs,
results
Verify components, sensors, instruments
Inspect the finishing, state, calibration status, labels, pipes,
tanks etc as discussed in previous parts of this module
Water
Slide 104 of 25
2013

Water treatment system inspection (1)
Checks may include:
Water
dead legs
filters
pipes and fittings
Ionic beds
storage tanks
by-pass lines
Slide 105 of 25
2013

Water treatment system inspection (2)
Checks may include:
Water
pumps
UV lights
sample points
reverse osmosis
valves
heat exchangers
Instruments, controls, gauges, etc.
Slide 106 of 25
2013

Other checks (1)
Material of construction
Weld quality
Hygienic couplings
Passivation procedure and records
Air breaks or Tundish
Water
Slide 107 of 25
2013

Other checks (2)
Pipes and pumps
hygienic couplings
welded pipes
hygienic pumps
hygienic
sampling points
acceptable floor
no leaks
Water
Slide 108 of 25
2013

Other checks (3)
Check condition of equipment
Staining on
water storage
tanks
Corrosion on plates of heat exchangers

indicates possible contamination
Water
Slide 109 of 25
2013

Other checks (4)
Maintenance records, maintenance of pump seals and O rings
Water
Slide 110 of 25
2013

Other checks (5)
Air filters
Integrity
testing
Sterilization
and replacement
frequency
Check
Water
burst discs
Slide 111 of 25
2013

Other checks (6)
Temperature-compensated conductivity meters
Influence of plastic pipe adhesive on TOC
Non-condensable gases in pure steam
Water
Slide 112 of 25
2013

Other checks (7)
UV light monitoring performance and lamp life and
intensity
Validating ozone dosage
Specifications for acids, alkalis for DI and sodium chloride
for water softener
Normally open and normally closed valves
Water
Slide 113 of 25
2013

Documentation review may include:
Qualification protocols and reports
System review
Change control request (where applicable)
Requalification (where applicable)
QC and microbiology test results and trends, OOS and OOT
Procedures and records
Water
Slide 114 of 25
2013

Sampling (1)
Review the sampling procedure (SOP) with a sampling plan
(user and sampling points)
Sample integrity must be assured
Sampler training
Sampling point , sample size, sample container and label
Sample transport and storage
When is the test started?
Test method is the filtration method used? Which media?
Water
Slide 115 of 25
2013

Sampling (2)
Verify compliance with the procedure and plan
Ensure that samples were taken and not skipped
Review trends
Alert and action limits, 2 sigma
OOS, OOL, OOT results

Investigations and CAPA
Water
Slide 116 of 25
2013

Testing
Review method verification
Chemical testing
Microbiological testing
test method
types of media used preferred R2A
How was the media sterilized validated procedure
incubation time and temperature
objectionable and indicator organisms
Manufacturers specifications
Water
Slide 117 of 25
2013

Suggested bacterial limits (CFU /mL)
See Pharmacopoeia
Sampling location
Target
200
Alert
Action
300
500
Post multimedia filter
100
300
500
Post softener
100
300
500
Post activated carbon

filter
Feed to RO
50
300
500
20
200
500
RO permeate
10
50
100
Points of Use
10
100
Raw water
Water
Slide 118 of 25
2013

Pyrogens and endotoxins
Where required, verify testing for pyrogens and endotoxins
Pyrogen : When injected into mammals will give rise to fever
Endotoxins are pyrogenic, come from Gram negative bacterial cell
wall fragments
Detect endotoxins using a test for lipo-poly-saccharides (LPS)
rabbit test detects pyrogens
LAL test detects endotoxins
Ultra-filtration, distillation and RO may remove pyrogens
Water
Slide 119 of 25
2013

Group Session
You are given a schematic drawing of a water system to discuss. List any
problems you identify and discuss their solutions
IN C O R R E C T W A T E R T R E A T M E N T PL A N T
Water
Slide 120 of 25
2013

Group Session
M O D IF IE D W A T E R T R E A T M E N T PL A N T
Water
Slide 121 of 25
2013

Group Session
Water
1.
Integrity test for vent filter of PW storage tanks and WFI storage tanks have been done
(total 4 storage tanks), but it can not be ensured the link and match of the filter integrity
report against the filter/housing filter itself. No ID filter/housing on integrity report
2.
Vent filter handling is stated on doc SOP ENG-UT/MSO/LS/032, It is not mentioned whether the
integrity tested filter (with pass integrity test status) will be re-used for the next certain period or
replaced with the new one.
If it is prolong used, the cycle of usage should be identified, controlled, justified and documented
3.
Integrity test of vent filter is executed for every 6 months, last testing was June 2014.
There is no test integrity record for Jan 2014 (the previous 6 month prior to June 14)
4.
Integrity test report of vent filter is complied with singles page. It is not attached in proper form,
so the potential to page missing.
There is no approval from checker, just approved by single operator. Double approved Quality
team (QA) is really recommended since this is product quality direct impact
Slide 122 of 25
2013

Group Session
5.
Observation on Raw water plant

There is no marking of acceptance criteria pressure Magnehelic
Some marking of water direction flow is missing and half was blur
6.
The monitoring time for recording 10 micron filter in DRW installation is not mentioned. SOP ENG15/MSO/LS/026
7.
8.
Water
Documentation of Monitoring system of DRW filter is not equipped by acceptance criteria so that
operator know whether it is meet spec or OOS.
Marking of acceptance criteria pressure on Magnehelic is not in place
Some piping direction was found in Blur condition, can not see clearly
The pressure monitoring of DRW Filter 08/DRW-F-234 was OUT OF ORDER STATUS. Out of order
label was in place, but its filtration system was still used for filtering process as feed water to PW
generator
Slide 123 of 25
2013

Group Session
Log book filter monitoring ENG-UT/FOR/086 are equipped with star marking. The issue was
happen on recurrences mode from 1-20 Oct 2014. On that issue, there is no documented
investigation for closing the issue
10.
Alert limit of conductivity on PW generator has not yet established

The control data just using action limit only.
11.
Alert limit or action limit of PW quality (etc: conductivity) is not conected to proper sound/light alarm to
Room supervisor or out side area of water system room
12.
All calibration labels including probe sensor, display, pressure transmitter, temperature sensor of PW
Generator/Christ Osmotron are over due
13.
Challenge of password level authorization on PW Generator Osmotron was done during observation. It
didnt represent any pass world level in place. All people during inspection can enter osmotron PLC
system using the same password. While the SOP has already been available
14.
SOP of cool loop sanitation has been available, defined frequency is every 3 months using Hydrogen
peroxide.
The record of the last 3 months has not yet shown to the auditor.
The evidence of residual H2O2 is not documented
Water
Slide 124 of 25
2013

Group Session
Log book filter monitoring ENG-UT/FOR/086 are equipped with star marking. The issue was
happen on recurrences mode from 1-20 Oct 2014. On that issue, there is no documented
investigation for closing the issue
10.
Alert limit of conductivity on PW generator has not yet established

The control data just using action limit only.
11.
Alert limit or action limit of PW quality (etc: conductivity) is not conected to proper sound/light alarm to
Room supervisor or out side area of water system room
12.
All calibration labels including probe sensor, display, pressure transmitter, temperature sensor of PW
Generator/Christ Osmotron are over due
13.
Challenge of password level authorization on PW Generator Osmotron was done during observation. It
didnt represent any pass world level in place. All people during inspection can enter osmotron PLC
system using the same password. While the SOP has already been available
14.
SOP of cool loop sanitation has been available, defined frequency is every 3 months using Hydrogen
peroxide.
The record of the last 3 months has not yet shown to the auditor.
The evidence of residual H2O2 is not documented
Water
Slide 125 of 25
2013

Group Session
Water
15.
Label of Out of Order is not using registered label
16.
Inconsistency on numbering Sampling point.
17.
Period 1-14 Oct 14, record of UV intensity meter is OOS (just reached 6%).
There is no documented DVR/investigation/similar adequate doc provided.
Request more info: need to investigate whether any RISK assessment in place in respect to product quality
since the UV is DIRECT impact CPP controlled device to eliminating Ozon
18.
Challenge test to control performance of AUTHOMATIC TLV Valve placed in production (user point) during
OZON process process is not in place
The related risk assessment in respect to any unperformed AUTHOMATIC TLV is not provided.
The qualification just done on annual basis. There is no guaranty for months before re-qualification
19.
Acceptance CRITERIA of Ozon concentration prior to be used by production has not established yet
20.
There is no record for ensuring of OZONE contacted time is not less than 3 hours as per required by SOP ENGUT/MSO/LS/009.
It is recommended to develop study for effective OZONE contacted time
Slide 126 of 25
2013

Group Session
21.
Sampling point no. 17 is not equipped by proper sampling valve, the position of sampling
point is not within looping system which represent PW looping condition
22.
Probe conductivity of multi steel water for producing WFI was not calibrated
23.
Recommendation:
The velocity of PW distribution is not in line with HAS and Local FDA requirements. 3000 liter/hours is
not enough for providing turbulence flow during distribution.
A risk assessment needs to be develop if the manufacturer still used their own spec
Water
Slide 127 of 25
2013

Group Session
2
The timing for introducing concentrated chlorination solution has not defined yet (SOP ENG UT/SOP/PM/030. This
condition has to describe chlorine concentration, initial tank condition before adding the concentrated chlorine in
respect to target dose since there is no testing of residual chlorine after treatment of chlorination itself
Daily monitoring of industrial RO unit is not equipped by acceptance criteria so that conclusion (pass/fail) of that monitoring
cannot be taken. It is important data for taking further improvement. This unit is belong Darmawans control
The usage of 20 microns filters can not be traced back since there is no documented link data due to details profile of used
filter such batch no, lot no, type and other related info since there is no testing of incoming filter, CoA is just used for filter
quality justification
1.
5
Water
2.
SOP ENG UT/SOP/PM/026, monitoring of DRW filter 20 microns filters, 12/1 2014 has 0,2 Pa while the acceptance
requirements is 0,3 pa
There is no appropriate column for describing P on before and after filtration (DRW) so that the operators calculate by
themselves without proper documentation. The record of individual filter is in place
Slide 128 of 25
2013

Group Session
6
There are no measurement devices to ensure the filtration performance of 1 filters. So on that reason, there is no
performance monitoring record of that particular filters
The frequency of filter changes are also not defined impacted by above reasons
There is no qualification label in PW generator unit.

It is suggested to perform re-qualification after usage of some period of time
Cold loop system:

UV intensity meter is not recorded, the same issue is also happen for UV working hours
10
Water
There is no in place technique to check the turbulence of PW inside of distribution piping. The appropriate flow meter is not in
place
Alert limit and action limit of conductivity are in place but the operator can change such water CQAs and CPPs without getting
authorization from related manager. Password management needs to re-change the password and re-training
Slide 129 of 25
2013

Group Session
Water
11
The cold loop report ENG- UT/FOR/PM/026 has not yet approved by QA but the PW itself has been distributed into
production area.
QA approved is required as per established SOP since this is CRITICAL step which needs quality people decision.
The related form has been established
12
Challenge test of main distribution valve after cold sanitation is not in place. There is no adequate system to ensure that the
valve is always working properly while its valve is not equipped by the periodic qualification.
13
Venting filters on storage tank:

The usage of 0,2 microns filters can not be traced back since there is no documented link data due to details profile of
used filter such batch no, lot no, type and other related info since there is no integrity testing of incoming filter, CoA is just
used for filter quality justification
The sequence activities for handling of filter change filters has considered cross contamination issues, but the SOP has not
up dated yet as per the actual handling
Slide 130 of 25
2013

Group Session
Water
14
The sequence of QC sampling time and PW distribution sanitation time is not representing worst case condition,
since it is only show the best case condition. QC sampling is in Tuesday while sanitation is Sunday
15
Ozone meter for checking residual ozone is not in place, but the operator use other system for ensuring there is not residual
ozone inside of PW. After ozonization, the PW is drained, but there is no record & evidence in place for ensuring that the PW
tank is empty before refill the new PW
Slide 131 of 25
2013

Group Session
Water
Slide 132 of 25
2013

TOT Water For Pharmaceutical Use - Part 1

Caricato da

Informazioni sul documento

Descrizione originale:

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

TOT Water For Pharmaceutical Use - Part 1

Caricato da

Copyright:

Formati disponibili

Water for Pharmaceutical Use

WHO Technical Report Series

Supplementary Training Modules on

Water for Pharmaceutical Use

Water for Pharmaceutical Use

APIs, finished products, etc.

GMP for design, installation, operation of systems

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Contaminants, microbial and chemical quality

Micro test results require incubation periods therefore results later

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

System performance, storage and distribution systems

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Which grade of water is suitable for a particular stage?

Let's look at types of water and indicate their use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Which type of water?

Preparation of injectable products

Final rinse of equipment after

Final rinse of equipment and

Water for Pharmaceutical Use

Specific types of water for processes and dosage forms

Supplementary Training Modules on

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

excess water recycled

air break to drain

Water for Pharmaceutical Use

Water for Pharmaceutical Use

"soft" water to deioniser

brine and salt tank

zeolite water softener

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Water for Pharmaceutical Use

Control microbiological contamination of sand filters, carbon

Water for Pharmaceutical Use