tot water for pharmaceutical use - part 1.ppt
Post on 29-Jan-2016
47 Views
Preview:
TRANSCRIPT
Water | Slide 1 of 25 2013
Water for Pharmaceutical Use
WHO Technical Report Series No 970, 2012. Annex 2
Water | Slide 2 of 25 2013
GMP Principle & Target AVOIDING
“MIX UP” & “CROSS CONTAMINATION”
Supplementary Training Modules on Good Manufacturing Practice
GMP Approach
“Systematic & SCIENTIFIC WAY” & “RISK ASSESMENT” with Patient Safety
Main Orientation
Water | Slide 3 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 for Pharmaceutical Use
Water | Slide 4 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 for Pharmaceutical Use
1.1.1 – 1.1.2
Water | Slide 5 of 25 2013
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)
Water for Pharmaceutical Use
1.1.3
Water | Slide 6 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 for Pharmaceutical Use
Water | Slide 7 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 water’s chemistry and contaminants, influenced by, e.g. rainfall, erosion, pollution, dissolution, sedimentation, decomposition
Water for Pharmaceutical Use
Water | Slide 8 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 for Pharmaceutical Use
Water | Slide 9 of 25 2013
Contaminants of water (2)
Problem minerals
Calcium, magnesium, copper, aluminium, heavy metals, arsenic, lead, cadmium, nitrates
Iron, manganese, silicates, carbon dioxide
Hydrogen sulfide
Phosphates
Water for Pharmaceutical Use
Water | Slide 10 of 25 2013
Contaminants of water (3)
Microorganisms – Biofilm formation
Protozoa– Cryptosporidium– Giardia
Bacteria– Pseudomonas– Gram negative, non-fermenting bacteria– Escherichia coli and coliforms
Water for Pharmaceutical Use
Water | Slide 11 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 for Pharmaceutical Use
Water | Slide 12 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"
Water for Pharmaceutical Use
1.2.1
Water | Slide 13 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
– Micro test results require incubation periods therefore results later after already used
Water for Pharmaceutical Use
1.2.2
Water | Slide 14 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)
Water for Pharmaceutical Use
1.2.3. – 1.2.4.
Water | Slide 15 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 for Pharmaceutical Use
2.1. – 2.3.
Water | Slide 16 of 25 2013
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
Water for Pharmaceutical Use
2.4. – 2.5.
Water | Slide 17 of 25 2013
Water quality specifications
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 for Pharmaceutical Use
3.
Water | Slide 18 of 25 2013
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
Water for Pharmaceutical Use
3.2.1., 3.2.3., 3.2.6.
Water | Slide 19 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 for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 20 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 for Pharmaceutical Use
3.3.1.
Water | Slide 21 of 25 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
Water for Pharmaceutical Use
3.4.1. – 3.4.3.
Water | Slide 22 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 for Pharmaceutical Use
3.5.1 – 3.5.4.
Water | Slide 23 of 25 2013
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
Water for Pharmaceutical Use
4.1. – 4.2.
Water | Slide 24 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
Water for Pharmaceutical Use
4.3. – 4.5.
Water | Slide 25 of 25 2013
Complete the table
Water for Pharmaceutical Use
UseWhich 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
?
?HPW
?Potable water
Water | Slide 26 of 25 2013
Water purification systems: So far:
Principles for pharmaceutical water systems
Water quality specifications– 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 for Pharmaceutical Use
Water | Slide 27 of 25 2013
Water for Pharmaceutical
Use
Part 2 Water purification,
storage and distribution
Supplementary Training Modules on Good Manufacturing Practice
WHO Technical Report Series No 970, 2012. Annex 2
Water | Slide 28 of 25 2013
Objectives
To examine the basic technology and requirements for:
Water purification systems
Storage and distribution requirements
Sanitization
Water for Pharmaceutical Use
5. - 6.
Water | Slide 29 of 25 2013
Water purification systems
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
Water for Pharmaceutical Use
5.1.1 – 5.1.2.
Water | Slide 30 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)
Water for Pharmaceutical Use
5.1.1 – 5.1.2.
Water | Slide 31 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
– the total life-cycle costs
Water for Pharmaceutical Use
5.1.1 – 5.1.2.
Water | Slide 32 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 for Pharmaceutical Use
5.1.3
Water | Slide 33 of 25 2013
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.
Water for Pharmaceutical Use
5.1.4
Water | Slide 34 of 25 2013
Pre-treatment steps
Primary filtration and multimedia filter
Coagulation or flocculation
Desalination
Softening
Water for Pharmaceutical Use
Water | Slide 35 of 25 2013
raw water in
« S” trap to sewer
Water is kept circulating
To water softener & DI plant
Pretreatment – schematic drawing
cartridgefilter
5 micrometers
activatedcarbon
filter
spray ball
break tank
air break to draincentrifugal pump
air filter
floatoperated
valvesand filter
excess water recycledfrom deioniser
Water for Pharmaceutical Use
Water | Slide 36 of 25 2013
Water pre-treatment complex in a pre-treatment room
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 37 of 25 2013
brine and salt tank
brine
"hard" waterin
zeolite water softener-exchanges-Ca and Mg for Na
drain
"soft" water to deioniserby pass valve
Water Softener – schematic drawing
Water for Pharmaceutical Use
Water | Slide 38 of 25 2013
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 for Pharmaceutical Use
Water | Slide 39 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
Water for Pharmaceutical Use
5.2.1 – 5.1.2.
Water | Slide 40 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
Water for Pharmaceutical Use
5.2.3. – 5.2.5.
Water | Slide 41 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 for Pharmaceutical Use
5.2.6. – 5.2.8.
Water | Slide 42 of 25 2013
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:
– back-flushing, chemical or thermal sanitization and frequent regeneration, continuous waterflow
Water for Pharmaceutical Use
5.2.10. – 5.2.11.
Water | Slide 43 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
Water for Pharmaceutical Use
5.2.9.
Water | Slide 44 of 25 2013
Production of Purified Water (PW) (1)
Use appropriate, qualified
methods to produce PW.
Includes: Ion exchange,
Reverse Osmosis,
Ultrafiltration and/or
EDI and distillation
Water for Pharmaceutical Use
5.3.1.
raw water
High pressure
Feedwater
underpressure
Reje
ctw
ater
Sem
i-perm
eab
lem
emb
rane
Perm
eate
water
drain or recycle
Low pressure
Purified water
Water | Slide 45 of 25 2013
Factors to consider in URS for PW: – feed-water quality (and variation over seasons) and water-
quality 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.
Water for Pharmaceutical Use
5.3.2.
Water | Slide 46 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
Water for Pharmaceutical Use
5.3.3
Water | Slide 47 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
Water for Pharmaceutical Use
5.3.4.
Water | Slide 48 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
Water for Pharmaceutical Use
5.4.1. – 5.4.2
Water | Slide 49 of 25 2013
Branch
Branch
2nd stage buffer tank
Cartridgefilter 1 µm
Second stage RO cartridge
First stage filtrate feeds second stage RO with excess back to 1st stage buffer tank.
1st
stag
e re
ject
co
nce
ntr
ate
Air breakto sewer
Second stage reject water goes back to first stage buffer tank
Second stage RO watermeets Pharmacopoeia
standards Outlets or storage
1st stage buffer tank
Water from softener or de-ioniser
Water returns to 1st stage buffer tank
Typical 2-stage RO schematic
Hygienic pump
First stage RO cartridge
High pressure pump
Water for Pharmaceutical Use
Water | Slide 50 of 25 2013
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 for Pharmaceutical Use
5.5.1. – 5.5.3
Water | Slide 51 of 25 2013
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
Water for Pharmaceutical Use
6
Water | Slide 52 of 25 2013
Water for Pharmaceutical Use
6.
What are the main components in a water storage and distribution
system?
Water | Slide 53 of 25 2013
Water must be kept
circulating
Spray ball
Cartridgefilter 1 µm
Air breakto drain
Outlets
Hygienic pump
Optionalin-line filter
0,2 µm
UV light
Feed Water from
DI or RO
Heat Exchanger
Ozone Generator
Hydrophobic air filter& burst disc
Water for Pharmaceutical Use
Typical water storage and distribution schematic
Water | Slide 54 of 25 2013
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
Water for Pharmaceutical Use
6.1.1. – 6.1.3
Water | Slide 55 of 25 2013
Contact materials
Materials that come into contact with WPU should be appropriate
Includes: – pipework– valves and fittings– seals– diaphragms and – Instruments
Water for Pharmaceutical Use
6.2.1. – 6.2.2.
Water | Slide 56 of 25 2013
Contact materials – Considerations (1)
Compatibility
Prevention of leaching
Corrosion resistance
Smooth internal finishing
Jointing
Unions and valves
Water for Pharmaceutical Use
6.2.2.
Water | Slide 57 of 25 2013
Contact materials – Considerations (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 for Pharmaceutical Use
6.2
Water | Slide 58 of 25 2013
Contact materials – Considerations (3)
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 for Pharmaceutical Use
6.2
Water | Slide 59 of 25 2013
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
Water for Pharmaceutical Use
6.3.1. -.6.3.2.
Water | Slide 60 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)– Vent filters (type, testing, use of heat)– Pressure relief valves and burst discs (sanitary design)
Water for Pharmaceutical Use
6.4.3
Water | Slide 61 of 25 2013
Water for Pharmaceutical Use
Storage Vessel Considerations and components
Water | Slide 62 of 25 2013
Requirements for water distribution pipework
General considerations
Temperature control
Circulation pumps
Biocontamination control techniques
Water for Pharmaceutical Use
6.5.
Water | Slide 63 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
Water for Pharmaceutical Use
6.5.1.1. – 6.5.1.2.; 6.5.3.
Water | Slide 64 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
Water for Pharmaceutical Use
6.5.2.1. – 6.5.2.3., 6.5.3
Water | Slide 65 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
Water for Pharmaceutical Use
6.5.4..2
Water | Slide 66 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 for Pharmaceutical Use
6.5.4.2
Water | Slide 67 of 25 2013
Water for Pharmaceutical Use
Water | Slide 68 of 25 2013
Water for Pharmaceutical Use
What type of valves are these?
Water | Slide 69 of 25 2013
Biocontamination control techniques (2)
There should be no dead legs
Water scours dead leg
Dead leg:Measured from the ID pipe wall to centre line of the point-of-use valve where significant stagnation potential exists
Dead leg section
Flow direction arrows on pipes are important
Sanitary Valve
D
Water for Pharmaceutical Use
Water | Slide 70 of 25 2013
The growth of microorganisms can be inhibited by:
UV radiation
Maintain system <25°C or > 65°C
Periodic and routine sanitizing of the system e.g. with:
– water > 70 °C)– superheated hot water or clean steam– chemicals e.g. ozone
Water for Pharmaceutical Use
6.5.4.2.
Water | Slide 71 of 25 2013
Water for Pharmaceutical
Use
Part 3: Operational
considerations
Supplementary Training Modules on Good Manufacturing Practice
WHO Technical Report Series No 970, 2012. Annex 2
Water | Slide 72 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 for Pharmaceutical UseWater for Pharmaceutical Use
7.
Water | Slide 73 of 25 2013
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 level of documentation and compliance with VMP
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.1
Water | Slide 74 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 for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 75 of 25 2013
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)
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 76 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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 77 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 for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 78 of 25 2013
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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 79 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 with the SOPs
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 80 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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.2
Water | Slide 81 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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.3.1. – 7.3.2.
Water | Slide 82 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 for Pharmaceutical UseWater for Pharmaceutical Use
7.3.1. – 7.3.3.
Water | Slide 83 of 25 2013
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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.4
Water | Slide 84 of 25 2013
System reviews
Regular intervals by a team (from engineering, QA, microbiology, operations and maintenance) and cover:
– 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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.5.1.
Water | Slide 85 of 25 2013
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
Water for Pharmaceutical UseWater for Pharmaceutical Use
7.5.2.
Water | Slide 86 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 purification systems
Water storage and distribution systems– Operational considerations
In Part 4 discuss approaches to inspection of water systems
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 87 of 25 2013
Supplementary Training Modules on Good Manufacturing Practice
WHO Technical Report Series No 970, 2012. Annex 2
Part 4:
Inspection of water purification systems
Water | Slide 88 of 25 2013
I start with:
As much as I learn, as much as I don’t know
Supplementary Training Modules on Good Manufacturing Practice
Water | Slide 89 of 25 2013
Supplementary Training Modules on Good Manufacturing Practice
The Angle point of This Training session :
cGMP Compliance, QA & Inspector Perspective for Water
System
instead of Technical Construction perspective
Water | Slide 90 of 25 2013
GMP Principle & Target AVOIDING
“MIX UP” & “CROSS CONTAMINATION”
Supplementary Training Modules on Good Manufacturing Practice
GMP Approach
“Systematic & SCIENTIFIC Based” & “RISK ASSESMENT” with Patient Safety
Main Orientation
Water | Slide 91 of 25 2013
Supplementary Training Modules on Good Manufacturing Practice
Chapter 4Pretreatment
Options
Chapter 1Introduction Chapter 10
Commissioning and Qualification
Chapter 9Instrumentation &
Control
Chapter 8Storage and Distribution
Systems
Chapter 11Appendix
Chapter 2Key Design
Philosophies
Chapter 7 Pharmaceutical
Steam
Chapter 6Final Treatment
Options: Water For Injection (WFI)
Chapter 5Final Treatment Options: Non-Compendial &
Compendial Purified Water
Chapter 3Water Options and
System Planning
Water | Slide 92 of 25 2013
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 (non-compendial 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
Key Design & PhilosophiesKey Design & Philosophies
Water | Slide 93 of 25 2013
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 (non-compendial 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
Key Design & PhilosophiesKey Design & Philosophies
Water | Slide 94 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 for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 95 of 25 2013
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 96 of 25 2013
Objectives
To understand:
The specific requirements when inspecting water systems, including associated documentation
Water system inspection techniques and approaches
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 97 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 for Pharmaceutical Use
8.
Water | Slide 98 of 25 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.
Water for Pharmaceutical Use
8.
Water | Slide 99 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 for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 100 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 for Pharmaceutical Use
Water | Slide 101 of 25 2013
Documentation should reflect information on: (1)PipelineValves (non-return type)Breather pointsCouplingsPipe slopeVelocitiesSampling pointsDrain points InstrumentationFlow rates
Water for Pharmaceutical Use
Water | Slide 102 of 25 2013
Documentation should reflect information on: (2)Specification for each system element Standard procedures for use System changesRoutine and non-routine maintenance Investigations and corrective action Validation studiesChemical and microbiological specificationsSampling instructionsTest proceduresResponsible persons Training requirements
Water for Pharmaceutical Use
Water | Slide 103 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 for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 104 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 for Pharmaceutical Use
Water | Slide 105 of 25 2013
Water treatment system inspection (1)
Checks may include: – dead legs– filters – pipes and fittings– Ionic beds– storage tanks– by-pass lines
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 106 of 25 2013
Water treatment system inspection (2)
Checks may include: – pumps– UV lights– sample points– reverse osmosis– valves– heat exchangers– Instruments, controls, gauges, etc.
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 107 of 25 2013
Other checks (1)
Material of construction
Weld quality
Hygienic couplings
Passivation procedure and records
Air breaks or “Tundish”
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 108 of 25 2013
Other checks (2)
Pipes and pumps
– hygienic couplings
– welded pipes
– hygienic pumps
– hygienic sampling points
– acceptable floor
– no leaks
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 109 of 25 2013
Staining on water storage tanks
Corrosion on plates of heat exchangers indicates possible contamination
Other checks (3) Check condition of equipment
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 110 of 25 2013
Other checks (4) Maintenance records, maintenance of pump seals and O rings
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 111 of 25 2013
Air filters
Integrity testing
Sterilization and replacement frequency
Check burst discs
Other checks (5)
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 112 of 25 2013
Other checks (6)
Temperature-compensated conductivity meters
Influence of plastic pipe adhesive on TOC
Non-condensable gases in pure steam
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 113 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 for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 114 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 for Pharmaceutical Use
Water | Slide 115 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 for Pharmaceutical Use
Water | Slide 116 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 for Pharmaceutical Use
Water | Slide 117 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
– Manufacturer’s specifications
Water for Pharmaceutical Use
Water | Slide 118 of 25 2013
Suggested bacterial limits (CFU /mL)
See PharmacopoeiaSampling location Target
Alert Action
Raw water 200 300 500
Post multimedia filter 100 300 500
Post softener 100 300 500
Post activated carbon filter
50 300 500
Feed to RO 20 200 500
RO permeate 10 50 100
Points of Use 1 10 100
Water for Pharmaceutical Use
Water | Slide 119 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 for Pharmaceutical Use
Water | Slide 120 of 25 2013
I N C O R R E C T W A T E R T R E A T M E N T P L A N T
Group Session
You are given a schematic drawing of a water system to discuss. List any problems you identify and discuss their solutions
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 121 of 25 2013
M O D I F I E D W A T E R T R E A T M E N T P L A N T
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
Water | Slide 122 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
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
Water | Slide 123 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
5.Observation on Raw water plantThere 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 ENG-15/MSO/LS/026
7.
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 placeSome piping direction was found in Blur condition, can not see clearly
8.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
Water | Slide 124 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
9Log 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 establishedThe 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 didn’t 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 for Pharmaceutical UseWater for Pharmaceutical Use
9Log 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 establishedThe 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 didn’t 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 126 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
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 placeThe 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 ENG-UT/MSO/LS/009.It is recommended to develop study for effective OZONE contacted time
Water | Slide 127 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
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 128 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
2The 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
3Daily 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 Darmawan’s control
4The usage of 20 micron’s 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
5
1. SOP ENG UT/SOP/PM/026, monitoring of DRW filter 20 micron’s filters, 12/1 2014 has ∆ 0,2 Pa while the acceptance requirements is ˃ 0,3 pa
2. 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
Water | Slide 129 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
6There are no measurement devices to ensure the filtration performance of 1 µ filters. So on that reason, there is no performance monitoring record of that particular filtersThe frequency of filter changes are also not defined impacted by above reasons
7There is no qualification label in PW generator unit.It is suggested to perform re-qualification after usage of some period of time
8 Cold loop system:UV intensity meter is not recorded, the same issue is also happen for UV working hours
9There is no in place technique to check the turbulence of PW inside of distribution piping. The appropriate flow meter is not in place
10Alert 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
Water | Slide 130 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
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
12Challenge 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 micron’s 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 justificationThe 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
Water | Slide 131 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
14The 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
15Ozone 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
Water | Slide 132 of 25 2013
Group Session
Water for Pharmaceutical UseWater for Pharmaceutical Use
top related