1. Supaporn Phumiamorn 17-18 Jan, 2006
Water System
GMP course
Supaporn Phumiamorn
17-18 Jan, 2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

2. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Topic
Water system
- Objectives and Principles
- Storage, Treatment
- Contaminants, Sampling
Water system inspection
Supaporn Phumiamorn, GMP course, Jan,2006

3. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Objectives
- Introduction to water for pharmaceutical use
- Sources and types of water for
pharmaceutical use
- Storage of bulk, untreated raw water
- Pre-treatment of water
Supaporn Phumiamorn, GMP course, Jan,2006

4. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Principles
Like any starting material, water must conform to GMP norms.
It must be “potable and comply with WHO guidelines for drinking-water quality.
Supaporn Phumiamorn, GMP course, Jan,2006

5. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Principles
Potential for microbial growth
Systems must be properly validated
Water for parenteral use could not be contaminated with pyrogens or endotoxins
Specifications and periodic testing is required
Supaporn Phumiamorn, GMP course, Jan,2006

6. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Water hardness
Water hardness mg/L or ppm
Classification as CaCO3
Soft
Moderate
Hard
Very hard >180
Supaporn Phumiamorn, GMP course, Jan,2006

7. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Raw water storage
May be required prior to pre-treatment according to local circumstances
Check material of construction
- Concrete, steel are acceptable
but check corrosion
- Plastics or plastic linings may
leach
Supaporn Phumiamorn, GMP course, Jan,2006

8. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Raw water storage
Check cover
- to keep out insects, birds and animals
Check contamination
Supaporn Phumiamorn, GMP course, Jan,2006

9. pharmaceutical processes
Types of water used in
pharmaceutical processes
Water for Injections – PFW & WFI
Softened Water
Water for Final Rinse
Pure, or Clean Steam
Purified Water
Water for Cooling Autoclaves
Water used as an ingredient in the formulation of pharmaceutical products must be either of the purified water type or must be water for injections.
The most common type of water in use in a pharmaceutical factory is purified water. This is used as an ingredient for manufacture of non-sterile pharmaceuticals. It is described in pharmacopeias.
The highest quality is Water For Injections. Water for Injections is used in parenteral products. It is also described in pharmacopeias. In bulk, this type of water is also called Pyrogen Free Water, or PFW, and if sterilized, it is called Sterilized Water for Injections. For other purposes, other types of water may also be used.
Besides potable water, there is softened water, which has had its Calcium and Magnesium removed. Such a water can be used e.g. for first washing steps. Certain processes require special well-defined qualities of water.
“Water for Final Rinse” is used for rinsing equipment after washing. It must be of the same quality as the water used for manufacturing the product. In some countries this can be prepared using different equipment to the ingredient water. For example, ultra-filtered water may be used for rinsing equipment for parenteral use, but WFI must be used as the parenteral ingredient.
Pure, pyrogen-free steam (called Clean Steam) is needed for sterilization, if the steam comes into contact with parenteral product or equipment that is going to be used for preparing parenteral products.
Steam, and Water for Cooling Autoclaves, are also used and must be properly prepared if they have the potential to come into contact with sterile or non-sterile product.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

10. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Pre-treatment steps
Primary filtration and multi-media filter
Coagulation of flocculation
Desalination
Softening
Supaporn Phumiamorn, GMP course, Jan,2006

11. Water pre-treatment complex
External raw water
storage
These photographs illustrate initial raw water storage and softening.
The top photograph shows a large scale storage tank, with automatic chlorine dosing.
The bottom photograph shows a water pre-treatment room with a water softener in place. In the foreground is the zeolite exchange column and in the background are the brine tanks used to recharge the zeolite column. The equipment is well laid-out, and the water treatment room looks well-organized and clean. There do not appear to be any leaks from pumps or pipes. Please note it is important that equipment is tagged, lines are marked and labeled with direction of flow and instruments are calibrated.
These rooms do not need to be environmentally controlled or the surfaces prescribed, but in this example the surfaces are smooth and impervious, which assists cleaning. The lighting levels should be good, allowing easy checking of instruments, recording of data and maintenance of equipment.
Pretreatment room
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

12. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
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 anti-microbial.
Supaporn Phumiamorn, GMP course, Jan,2006

13. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Why purify raw water?
Although reasonably pure, it is always variable
Seasonal variations may occur in water
Some regions have very poor quality water
Must remove impurities to prevent product contamination.
Control microbes to avoid contaminating products
(The trainer should emphasize that raw water, even from municipal supplies, needs to be purified before use for manufacture of pharmaceuticals, because the quality varies over time, according to seasonal variations and potable standards are not always met.)
Although reasonably pure, raw water from the sources described previously can be of variable quality with potable water from some regions of very poor quality, by pharmaceutical standards. Seasonal variations may occur and contamination may vary.
In some areas there are droughts and floods, in other areas winter, spring, autumn and summer weather can have an affect on raw water quality.
In many countries even tap water is not safe to drink.
Water from municipal reticulation systems needs to be purified because of variation in quality, microbial loads and natural seasonal variations. Manufacturers must remove impurities to prevent product contamination.
It is also important to control microbes to avoid contaminating products.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

14. 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
Micro-organisms
Contaminants of water:
Because of the wide variation in source and because of water’s unique chemical properties, which makes it the “universal solvent”, there is no pure water in nature. A wide variety of compounds may be present. There are more than 90 possible unacceptable contaminants of potable water listed by health authorities. The trainer can expand on other contaminants that are important, or on any local requirements that are relevant. For example, in some areas hormone-like compounds may be a problem.
Contaminants can be put into the following groups:
Inorganic contaminants, such as chloramines, magnesium carbonate, calcium carbonate and sodium chloride;
Organic contaminants, such as detergent residues, solvents and plasticizers;
Solids, such as clays, sols, cols and soils;
Gases, such as nitrogen, carbon dioxide and oxygen; and
Micro-organisms. These can be particularly troublesome because of the numbers that can grow in nutrient-depleted conditions. Bacteria may even multiply in pure water.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

15. Contaminants of water (2)
Treatment depends on water’s chemistry and contaminants, influenced by:
1. Rainfall 5. Evaporation
2. Erosion Sedimentation
3. Pollution Decomposition
4. Dissolution
Contaminants of water: (Contd.)
The type of treatment is influenced by the impurities in water. These vary because of effects such as:
Rainfall, which can dissolve acid from the atmosphere and pick up other contaminants, such as fouling from roofs upon which it collects;
Erosion, which introduces minerals, clays and soils;
Pollution, from the atmosphere and from groundwater contamination;
Dissolution, whereby minerals and solids slowly dissolve in the stored water;
Evaporation, which can concentrate and precipitate minerals;
Sedimentation, whereby dissolved minerals re-precipitate and block pipes and filters;
Decomposition, for example when contaminants arise from degraded pollutants.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

16. Contaminants of water (3)
Problem minerals
Calcium and magnesium
Iron and manganese
Silicates
Carbon dioxide
Hydrogen sulfide
Phosphates
Contaminants of water: (Contd.):
Calcium and magnesium are probably the two most common mineral contaminants. They cause water hardness discussed in another slide. Heating or boiling water can precipitate these minerals leaving behind a scale deposit.
Iron and manganese discolour water and can react with drug products, or act as catalysts in decomposition processes.
Silicates may interfere with distillation equipment.
Carbon dioxide picked up in the atmosphere can change the pH and hence the conductivity of water. Carbonates can cause precipitation of calcium, and carbonic acid can cause corrosion of water treatment systems.
In areas of thermal activity, the water may be contaminated with sulphides, which even at low levels cause a rotten egg odour.
Phosphates can also cause precipitation of metal ions and scaling, e.g. in boilers.
(The trainer can also point out any local mineral-related contaminants that may be relevant in the region. For example, in some areas radioactive minerals may be a problem. )
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

17. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Contaminants of water (4)
Further problem minerals
Copper
Aluminium
Heavy metals
Arsenic, lead, cadmium
Nitrates
Contaminants of water: (Contd.):
Copper contamination can arise from corrosion of copper piping.
Aluminium can pose a problem in the manufacture of dialysis products. It can be introduced from the flocculation treatment used to reduce sols and clays.
Heavy metals, particularly arsenic, may be problematic in wells in certain areas. Lead contamination can arise from tanks which have had lead solder repairs. Lead pipes are not recommended. Cadmium can also be an issue depending on the where the aquifer percolates.
Nitrates are an increasing problem for drinking water, but are easily removed by de-ionizers.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

18. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Contaminants of water (5)
Micro-organisms – Biofilm
Algae
Protozoa
Cryptosporidium
Giardia
Bacteria
Pseudomonas
Gram negative, non-fermenting bacteria
Escherichia coli and coliforms
Contaminants of water: (Contd.)
One of the major obstacles to successful treatment of water is the presence of micro-organisms. These are usually found in biofilms that develop on wet surfaces in almost any condition. The next slide explains how biofilm forms.
The major groups of contaminating micro-organisms are:
Algae: These arrive from raw water but can also grow where water is uncovered and there is a light source. Sometimes algae grow when UV lights lose their lethal effect and are emitting only visible light.
Protozoa: These include Cryptosporidium and Giardia. They can usually be easily filtered out since they are relatively large organisms.
Bacteria. Of these, the normal aquatic microflora cause the most problems. Most of these belong to the Pseudomonas family or are Gram negative, non-fermenting bacteria. Some of them easily pass through 0.2 micrometer filters and are known to cause disease. Other Gram negative bacteria that are objectionable are Escherichia coli and coli forms. These are indicator organisms pointing to faecal contamination.
Supaporn Phumiamorn, GMP course, Jan,2006
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

19. Water is kept circulating
Pretreatment – schematic drawing
float
operated
valve
To water softener & DI plant
excess water recycled
from deioniser
activated
carbon
filter
sand filter
air filter
spray ball
Water is kept circulating
raw water in
break tank
This schematic drawing is shown in handout and illustrates a typical storage and preliminary treatment system for water. Raw water arrives into a buffer or break tank via a level controlled valve. If there are further stages of treatment (such as DI or RO), the tank does not, generally, have to have sophisticated spray balls or air filters.
The water is pumped through a sand filter to remove large particles. This filter must be fitted with a back-flush facility, not shown here. The water then enters an activated carbon (AC) filter which removes organic impurities and chlorine. The AC filter can become heavily contaminated with bacteria. There should be some means of sanitizing it, such as a steam supply. Chemicals are generally not used to disinfect activated carbon filters. The water is then “polished” through a 5 micron filter before it enters the next treatment step. If there is no demand for the water it must be re-circulated to the buffer tank.
Water that is kept constantly circulating is less likely to grow bacteria, because they cannot settle and form a “biofilm”. All equipment such as pumps, pipes and tanks should be stainless steel wherever possible. Plastic should be avoided. Plasticizers may leach and this can result in out-of-specification Total Organic Carbon (TOC) levels. Adhesives used for welding plastic pipes may also leach into the water and cause problems.
cartridge
filter
5 micrometers
centrifugal pump
air break to drain
« S” trap to sewer
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

20. Plumbing Source water chlorination 1.Filtration .
Pre-treatment
Distillation S S S S S
Holding
Take
 80oc
chlorination S
1.Filtration
-Sand filter
-Charcoal filter
-Cartridge filter . S S
Pump
* S: Sampling
2. Primary water treatment
Water solftener
Deionizer
Reverse Osmosis

21. Water Softener – schematic drawing
brine and salt tank
brine
"hard" water in
zeolite water softener
exchanges
Ca and Mg for Na
drain
"soft" water to deioniser
by pass valve
This schematic drawing give in handout If the pharmaceutical manufacturer’s water supply is “hard” it needs to be “softened” by removal of calcium and magnesium salts.
Water is softened in a zeolite exchange column where the calcium and magnesium ions are exchanged for sodium. The sodium then has to be removed by de-ionization or reverse osmosis. When the zeolite reaches its exchange limit, it needs to be stripped of calcium and magnesium. This can be done using a brine solution, which exchanges sodium for calcium and magnesium, and the cycle starts again.
The inspectors should ensure that there is a proper procedure for the regeneration of the unit, and that the system is properly monitored and sanitized. The frequency of regeneration is something that the inspectors should ask the manufacturer to justify.
เอกสารประกอบการอบรมเรื่อง หลักเกณฑ์และวิธีการที่ดีในโรงงานผลิตชีววัตถุ

22. Water purification
RO / Deionizer
Cartridge filtration

23. Water purification Reverse Osmosis Remove particles, bacteria,
pyrogen, organic, inorganic ions and silica

24. Water purification Deionization
Remove organic, inorganic ions, silica and carbon dioxide

25. Water purification Distillation Remove particles,
bacteria, pyrogen, organic, non-volatile, inorganic ions
and silica for WFI

26. Water purification
Ultrafiltration
Kill bacteria
and breakdown TOC

27. Auto DI
RO/Auto DI
2 stages RO
Purified water

28. -Conductivity meter
- pH meter
-Temperature meter(80oC)
-Alarm meter

29. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Sampling
There must be a sampling procedure.
Sample integrity must be assured.
Sampler training
Sample point
Sample size
Sample container
Supaporn Phumiamorn, GMP course, Jan,2006

30. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Sampling
Sample label
Sample storage and transport
Arrival at the laboratory
Start of test
Supaporn Phumiamorn, GMP course, Jan,2006

31. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Water for Injections
International pharmacopoeia requirements for WFI are those for purified water plus it must be free from pyrogens.
Usually prepared by distillation.
Storage time should be less than 24 hours.
Microbial limits must be specified.
Supaporn Phumiamorn, GMP course, Jan,2006

32. Pyrogens and endotoxins
Any compound injected into mammals which gives rise to fever is a “Pyrogen”.
Supaporn Phumiamorn, GMP course, Jan,2006

33. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
WFI testing
Microbial test, < 1 CFU/10 ml WFI
Endotoxin test, < 0.25 Eu/ml
Total organic count, < 500 g/l
Supaporn Phumiamorn, GMP course, Jan,2006

34. Water system inspection
Supaporn Phumiamorn, GMP course, Jan,2006

35. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Inspection plan
Water quality manual
- water system drawing
- validation
- sampling procedures, location and plan
- records of testing
- sanitation and maintenance
- schedules of maintenance
Supaporn Phumiamorn, GMP course, Jan,2006

36. Review water quality manual
A water quality manual is advisable.
A brief description of water systems is required.
Include drawings of the purification, storage distribution system.
Supaporn Phumiamorn, GMP course, Jan,2006

37. The manual should contain
Chemical and microbiological specifications
Sampling instructions
Test procedures
Responsible persons
Training requirements
Supaporn Phumiamorn, GMP course, Jan,2006

38. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Review validation
Validation for water systems
consists of 3 phases:
Phase 1: weeks
Phase 2: weeks
Phase 3: year
Supaporn Phumiamorn, GMP course, Jan,2006

39. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Phase 1
Investigational phase (2-4 weeks)
- DQ, IQ and OQ
- Develop
- operational parameters
- cleaning and sanitization
procedures and frequencies
- Sample daily at each point of use
-End of phase 1, develop SOPs for the
water system
Supaporn Phumiamorn, GMP course, Jan,2006

40. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Phase 2
Verifying control (4- 5 weeks)
- Demonstrate the system is in control
-Sampling as in phase 1
Supaporn Phumiamorn, GMP course, Jan,2006

41. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Phase 3
Verifying long- term control ( 1 year)
- Demonstrate the system in control over a long period of time
-Weekly sampling
Supaporn Phumiamorn, GMP course, Jan,2006

42. Conducting the inspection
Take the drawing and walk around the entire system
Check:
- dead legs - pumps
-filter - UV light
-pipe and fittings - sample points
-DI RO
-storage tank - non return valves
-by –pass lines - heat exchangers

43. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Check:
- stainless steel – PVC and most plastics not recommended
- water quality
- hygienic couplings
- passivation
- air breaks or “Tundish”
Supaporn Phumiamorn, GMP course, Jan,2006

44. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Check:
- condition and equipment corrosion on plates of heat exchangers indicates possible contamination
- maintenance records
Supaporn Phumiamorn, GMP course, Jan,2006

45. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
Check:
- air filter
- integrity testing, sterilization
- replacement frequency
- burst discs
Supaporn Phumiamorn, GMP course, Jan,2006

46. Supaporn Phumiamorn, GMP course, 17-18 Jan,2006
References
WHO,1997. Joint training on GMP for biological products in Thailand, 2-11 September, 1997
Chung Keel Lee, GMP and related topics, October, 2003.
Chung Keel Lee, Current GMP for biological products and its practical implementation, March, 2004.
FDA and WHO, GMP inspection workshop, June, 2004.
Supaporn Phumiamorn, GMP course, Jan,2006