This guide is designed to provide a valuable and
convenient information resource to aid in the design of
pharma water systems that are compliant with the
requirements of global pharmacopeias. It offers vital
information on topics including requirements for
source bulk waters, control of biofilms, and the three
stages of water systems.
GMP Requirements for Sterile Products manufacturingsurafel kebede
This training module is prepared based on (Annex 6. TRS 961, 2011) & trainees are highly recommended to read this document together with Annex 6. TRS 961, 2011.
What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
Contamination Control in Cleanrooms_Dr.A. AmsavelDr. Amsavel A
Basic’s of Contamination
Sources of Contamination
Environment Specification
Elements of Cleanroom Design and Qualification
Definitions
Control of Contaminations
People, Cleaning, Environment & Material
Operation, Monitoring and Control
Documents and Records
GMP Requirements for Sterile Products manufacturingsurafel kebede
This training module is prepared based on (Annex 6. TRS 961, 2011) & trainees are highly recommended to read this document together with Annex 6. TRS 961, 2011.
What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
Contamination Control in Cleanrooms_Dr.A. AmsavelDr. Amsavel A
Basic’s of Contamination
Sources of Contamination
Environment Specification
Elements of Cleanroom Design and Qualification
Definitions
Control of Contaminations
People, Cleaning, Environment & Material
Operation, Monitoring and Control
Documents and Records
Pharmaceutical HVAC (Heating, ventilating, and air conditioning; also heating...Palash Das
This slide is represent the HVAC design,qualification and operational approach. As we know HVAC is important system for maintaining clean room. This presentation is made based on the requirement of Pharmaceutical Industry. All parameter are considered based on the current guidelines aspect.
Experienced Quality Professional with a demonstrated history of working in the Top leading National pharmaceutical industries (Platinum, Bosch, Getz & Nabiqasim Pharma) of pakistan. Part of WHO & PIC/S Team.
Skilled in various function of Quality Assurance, Quality Management Sysytem,Validation & Qualification as described below.
1-Deviation Management System.
2-Change Control Management System.
3-Corrective & Preventive Action(CAPA).
4-Root Cause Analysis(Investigation).
5-Self Inspection (Level-I), GMP Inspection (Level-II), Internal Audit (Level-III).
6-Quality Risk Management System.
7-Market Complaint (Product Quality Defect).
8-Product Recall (Mock Recall).
9-Product Quality Review(APQR).
10-Management Review.
11-Supplier Qualification
12-ISO (9001,14001,45001 & 17025)
13-Validation Master Plan
14-Process Validation
15-Area & Equipment Qualification
16-Cleaning Validation
17-Calibration & Verification
18-Analytical Method Validation
Batch Manufacturing Record Auditing and Sop writing along with effective training sessions reagrding GMP.GDP.GLP & GSP.
A brief summary of Water System in pharmaceuticals including its production and distribution with regulatory and qualification requirements. This presentation gives a basic layout to non-engineering people a basic understanding of Water System in Pharmaceutical.
WHO Good Manufacturing Practice Requirements
Good Manufacturing Practice is the part of quality assurance that ensures that products are consistently manufactured and controlled to the quality standards appropriate to their intended use.
While the public considers municipal water to be “pure”, the pharmaceutical market considers municipal water (feedwater) just the starting point in producing pure water. Water is the most widely used excipient in pharmaceutical manufacturing, and pharmaceutical water is a multi-functional resource, crossing all disciplines in the pharmaceutical industry. Water is used as a raw material, solvent, ingredient, reagent, and clean-ing agent, and is produced in a variety of “pure” forms.
Pharmaceutical HVAC (Heating, ventilating, and air conditioning; also heating...Palash Das
This slide is represent the HVAC design,qualification and operational approach. As we know HVAC is important system for maintaining clean room. This presentation is made based on the requirement of Pharmaceutical Industry. All parameter are considered based on the current guidelines aspect.
Experienced Quality Professional with a demonstrated history of working in the Top leading National pharmaceutical industries (Platinum, Bosch, Getz & Nabiqasim Pharma) of pakistan. Part of WHO & PIC/S Team.
Skilled in various function of Quality Assurance, Quality Management Sysytem,Validation & Qualification as described below.
1-Deviation Management System.
2-Change Control Management System.
3-Corrective & Preventive Action(CAPA).
4-Root Cause Analysis(Investigation).
5-Self Inspection (Level-I), GMP Inspection (Level-II), Internal Audit (Level-III).
6-Quality Risk Management System.
7-Market Complaint (Product Quality Defect).
8-Product Recall (Mock Recall).
9-Product Quality Review(APQR).
10-Management Review.
11-Supplier Qualification
12-ISO (9001,14001,45001 & 17025)
13-Validation Master Plan
14-Process Validation
15-Area & Equipment Qualification
16-Cleaning Validation
17-Calibration & Verification
18-Analytical Method Validation
Batch Manufacturing Record Auditing and Sop writing along with effective training sessions reagrding GMP.GDP.GLP & GSP.
A brief summary of Water System in pharmaceuticals including its production and distribution with regulatory and qualification requirements. This presentation gives a basic layout to non-engineering people a basic understanding of Water System in Pharmaceutical.
WHO Good Manufacturing Practice Requirements
Good Manufacturing Practice is the part of quality assurance that ensures that products are consistently manufactured and controlled to the quality standards appropriate to their intended use.
While the public considers municipal water to be “pure”, the pharmaceutical market considers municipal water (feedwater) just the starting point in producing pure water. Water is the most widely used excipient in pharmaceutical manufacturing, and pharmaceutical water is a multi-functional resource, crossing all disciplines in the pharmaceutical industry. Water is used as a raw material, solvent, ingredient, reagent, and clean-ing agent, and is produced in a variety of “pure” forms.
The water to be used for the preparation of haemodialysis fluids needs treatment to achieve the appropriate quality. The water treatment is provided by a water pre-treatment system which may include various components such as sediment filters, water softeners, carbon tanks, micro-filters, ultraviolet disinfection units, reverse osmosis units, ultrafilters and storage tanks. The components of the system will be determined by the quality of feed water and the ability of the overall system to produce and maintain appropriate water quality.
Water for Pharmaceutical Use........pptxNazim Hussain
Pharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, qualified and maintained to ensure the reliable production of water of an appropriate quality.for pharmaceutical water systems.
Annex 1: Development of monographs for The International Pharmacopoeia Annex 2: WHO good manufacturing practices: water for pharmaceutical use Annex 3: Pharmaceutical development of multisource (generic) pharmaceutical products - point to consider
Annex 4: Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part.
Annex 5: Development of paediatric medicines: points to consider in formulation
Annex 6: Recommendations for quality requirements for artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredient.
Inspection of water systems
8.2 The following list identifies items and a logical sequence for a WPU system inspection or audit:
– a current drawing of the water system showing all equipment in the system from the inlet to the points of use along with sampling points and their designations;
– approved piping drawings (e.g. orthographic and/or isometric);
– a sampling and monitoring plan with a drawing of all sample points;
– training programme for sample collection and testing;
– the setting of monitoring alert and action levels;
– monitoring results and evaluation of trends;
– inspection of the last annual system review;
– review of any changes made to the system since the last audit and a check that the change control has been implemented;
– review of deviations recorded and their investigation;
– general inspection of system for status and condition;
– review of maintenance, failure and repair logs;
– checking calibration and standardization of critical instruments
Jogler is a Baton Rouge, Louisiana manufacturer of high quality Magnetic Level Gauges, Magnetostrictive Transmitters, Direct-Reading Level Gauges with armored shield, Sight Flow Indicators, Specific Gravity Analyzers, Point Level Switches and other accessories.
Product catalog for industrial electric heating and freeze protection solutions. Used for temperature maintenance or to prevent freezing of flowing fluids or gases in tanks, pipes, vessels, and lab equipment.
Within the METTLER TOLEDO Group, the Process Analytics division concentrates on analytical measurement solutions for industrial manufacturing processes. The division consists of two business units: Ingold and Thornton, both recognized leaders in their respective markets and technologies.
Ingold is a worldwide leader in pH, dissolved oxygen, CO2, conductivity and turbidity solutions for process analytical measurement systems
in chemical, food & beverage, biotechnology and pharmaceutical industries. Its core competence is high quality in-line measurement of these para- meters in demanding chemical process and hygienic and sterile applications. Thornton is the leader in pure and ultrapure water monitoring instrumentation used in semiconductor, microelectronics, power generation, pharmaceutical, and biotech applications. Its core competence is the in-line measurement of conductivity, resistivity, TOC, bioburden, dissolved oxygen and ozone in determining and controlling water purity.
The division recently expanded into Gas Analytics with a series of TDL analyzers offering unique in situ solutions.
Jogler is a manufacturer of process control instrumentation specializing in level control devices: site flow indicators, sight glass level indicators, magnetic level gauges, magnetostrictive transmitters, laser level transmitters and specific gravity analyzers. Jogler, LLC is a certified ASME boiler code facility and carries the U, UM and S stamps that are required via ASME boiler code section B31.1 and B31.3.
Proper process control plays a vital role in determining the flavor, foam stability, and color of the finished beer. The relative measurement sensors are exposed to high temperatures, and solid particles and turbidity constituents, and must be capable of surviving multiple CIP cycles.
Briskheat manufactures flexible surface heating elements and controls / accessories for unlimited applications. Petrochemical, semiconductor, food processing, biotech, aviation, steel, laboratory, power generation and many other industries have found their solution with Briskheat heating products. Products include Flexible Surface Heat Products, Heat Trace (Self-Regulating, Constant-Wattage & MI), Digital & Mechanical Temperature Controllers, Composite Curing Heating Products.
High quality magnetic level gauges, magnetostrictive transmitters, direct-reading level gauges with armored shield, sight flow indicators, specific gravity analyzers, point level switches and other accessories.
Thornton recently published a helpful guide for best practices in pure water measurement. It is entitled "Compliance by Design in Pharmaceutical Water Systems". The document provides an summary of water sources and contaminants, then continues with an outline of industry requirements for bulk waters. The production of pure water is dicussed, and recommendations for pharmaceutical water system instrumentation are provided.
Vaisala Indigo 200 series transmitters are host devices
for displaying measurement values from Vaisala Indigo
compatible probes and/or transmitting them to
automation systems through analog signals, Modbus
RTU communication or relays.
The LLT-1000 LIDAR Level Transmitter is a non-contact, laser based instrument that measures the level of dry solids and opaque liquids in silos, tanks, hoppers, and other vessels. 4-20 mA and relay outputs give the LLT-1000 the flexibility to be used in various control schemes.
For periodic pH measurements or redox measurements, this mobile pH meter is the ideal choice. It combines great durability and intuitive, one-handed operation with the high measurement confidence and diagnostics you expect from METTLER TOLEDO.
The DSA E-Scan is an automatic, bench-top critical angle refractometer with a digital readout and temperature-controlled sample chamber. It measures the critical angle of refraction of sample fluids which are directly correlated to various measurements including percent dissolved solids, Brix, and refractive index. The instrument is equipped with a menu-driven user interface and is factory calibrated and temperature compensated.
The Vaisala DL2000 data logger provides highly accurate and stable measurement of temperature and humidity, with an optional analog input channel for other parameters. Along with superior accuracy, the DL2000 data loggers record and store data at the point of measurement ensuring that no data is ever lost to power or network downtime.
The Thornton 5000TOCi Intelligent Sensor Management (ISM®) sensor provides continuous, fast, and reliable monitoring of TOC levels of reverse osmosis membranes, effectiveness of TOC destruct UV lamps, resin bed performance, organics shedding, and quality of final rinse water. With continuous on-line measurements, the 5000TOCi sensor ensures TOC excursions will not be missed.
Surface temperatures can be a difficult measurement. Special engineering and extensive testing of the Smart Sensor surface pad provides fast response and accurate surface measurement. Model 1500 shown above has been used extensively as the primary control element for freeze protection control loops. A retractable design that allows removal of the sensor while leaving the surface pad in place is also available. Smart sensor designs have be used to measure the skin temperature of vessels, pipes, boiler tubes, superheater tubes or where ever the process requires surface temperature measurement.
METTLER TOLEDO is the industry leader in analytical measurement solutions. Our dedication to continuously
improving the reliability and durability of our sensors, transmitters
and housings is recognized by thousands of customers. Pharmaceutical manufacturers and breweries the world over rely on our in-line dissolved oxygen systems for ensuring process safety and efficiency.
ProCal Primary Turbidity Standards are pre-diluted, factory certified, and ready for use with not only the HF scientific turbidimeter product line but with other manufacturer’s instrumentation. The ProCal no formazin formulation utilizes a preservative that enhances stability, yet is safe and biodegrades rapidly in aquatic environments.
EasyClean400 is versatile in its application. It offers multiple control possibilities and can be programmed extensively. Furthermore, a version for applications in explosion hazardous areas is available. The integration into a distributed control system (DCS) can be easily realized in a conventional way or via a Profibus® PA.
The ability of TDLs to interface directly to the process, which
eliminates the need for costly and high-maintenance sample
handling systems, gives them an inherent rapid speed of response. This makes them ideal for real-time dynamic measurement of process conditions.
The retractable housings are intended solely for measurement tasks in conjunction with the specified METTLER TOLEDO electrodes/sensors, namely pH and redox (ORP) combined electrodes as well as dissolved oxygen (DO) or conductivity sensors.
The Indian economy is classified into different sectors to simplify the analysis and understanding of economic activities. For Class 10, it's essential to grasp the sectors of the Indian economy, understand their characteristics, and recognize their importance. This guide will provide detailed notes on the Sectors of the Indian Economy Class 10, using specific long-tail keywords to enhance comprehension.
For more information, visit-www.vavaclasses.com
Model Attribute Check Company Auto PropertyCeline George
In Odoo, the multi-company feature allows you to manage multiple companies within a single Odoo database instance. Each company can have its own configurations while still sharing common resources such as products, customers, and suppliers.
This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
Ethnobotany and Ethnopharmacology:
Ethnobotany in herbal drug evaluation,
Impact of Ethnobotany in traditional medicine,
New development in herbals,
Bio-prospecting tools for drug discovery,
Role of Ethnopharmacology in drug evaluation,
Reverse Pharmacology.
Students, digital devices and success - Andreas Schleicher - 27 May 2024..pptxEduSkills OECD
Andreas Schleicher presents at the OECD webinar ‘Digital devices in schools: detrimental distraction or secret to success?’ on 27 May 2024. The presentation was based on findings from PISA 2022 results and the webinar helped launch the PISA in Focus ‘Managing screen time: How to protect and equip students against distraction’ https://www.oecd-ilibrary.org/education/managing-screen-time_7c225af4-en and the OECD Education Policy Perspective ‘Students, digital devices and success’ can be found here - https://oe.cd/il/5yV
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
1. BestPractice
Compliance by Design
in Pharmaceutical Water Systems
THORNTON
Leading Pure Water Analytics
Compliments of Alliance Technical Sales, Inc.
Clarendon Hills, IL USA | 630-321-9646 | www.alliancets.com
2. 2 METTLER TOLEDO Compliance by Design
This guide is designed to provide a valuable and
convenient information resource to aid in the design of
pharma water systems that are compliant with the
requirements of global pharmacopeias. It offers vital
information on topics including requirements for
source bulk waters, control of biofilms, and the three
stages of water systems.
Contents
Page
1. Initial Design Considerations 3
2. General Information on Water Sources and 3
Contaminants
2.1 Contaminants in water 4
2.2 Pharmacopeia requirements for source water 5
3. Production Requirements for Bulk Waters 5
3.1 Basic water system monitoring requirements 5
3.2 Purified Water (PW) - USP37 – NF32 6
3.3 Water for Injection (WFI) – USP37 – NF32 6
4. Biofilm 7
5. Designing and Engineering Pharmaceutical 7
Water Systems
5.1 Pre-treatment 7
5.2 Purification 8
5.3 Storage and distribution 9
6. Instrumentation Recommendations for 10
Pharmaceutical Water Systems
3. 3Compliance by Design METTLER TOLEDO
1 Initial Design Considerations
For the production of pharmaceutical waters, source water must be treated using a combination of
purification steps that are designed to remove specific types of impurities. The combination and order
of purification steps varies for every system, and several aspects need to be considered when designing
a pharmaceutical water system:
• Source water
- Quality
- Seasonal changes
- Microbial control methods
• Green engineering
• Risk factors to the end product
• Cost
- Capital
- Available resources
- Operating costs
No single design will meet every requirement or is guaranteed to produce the appropriate water quality.
A pharmaceutical water system must have the capability to deliver safe water consistently and
confidently, based on knowledge of source water and produced water, good engineering practices and
water system design, good monitoring/control programs, and proper sanitization/maintenance.
Figure 1: Sources of pharmaceutical waters
Water for
Injection
Purified Water Pure Steam Water for
Hemodialysis
CIP
Final
Rinse
Sterile Purified
Water
Sterile Water
for Injection
Sterile Water
for Installation
Bacteriostatic
Water for Injection
Sterile Water
for Irrigation
Drinking WaterDrinking WaterDrinking Water
2. General Information on Water Sources and
Contaminants
The water supply to a municipality for the production of drinking water can vary substantially depending
on whether it is ground or surface water and if it is in an area that is subject to seasonal variations or
drought/monsoon conditions. This guide considers ground and surface water and the contaminants that
can be found in those waters.
PharmaceuticalWaterSystems
• Required volume and quality of water
- Peak, average, shutdown volumes
- Types of water, compendial requirements
- Temperature
• Uses of water
- Compendial ingredient
- Cleaning/rinsing/washing
- Humidification
• Redundancy
• Future capacity
4. 4 METTLER TOLEDO Compliance by Design
PharmaceuticalWaterSystems
Table 1: Water sources for production of potable (drinking) water:
Ground waters Surface waters
Higher mineral content
Low organic levels
Higher hardness levels
Less temperature variation
Lower mineral content
Higher organic levels
Higher TDS levels
Wide temperature variations
Seasonal fluctuations
2.1 Contaminants in water
Due to wide variations in source waters and because of water’s unique chemical properties, there is no
pure water in nature. Water has unique chemical properties due to its polarity and hydrogen bonds. This
means it is able to dissolve, absorb, adsorb or suspend many different compounds. These include
contaminants that may represent hazards in themselves or that could react with the intended solution,
drug or product. There are more than 90 possible unacceptable contaminants in potable water which
are listed by government health authorities.
• Total dissolved solids (TDS)
• Total ionized solids and gases
Currently available purification processes and technologies effectively remove certain of the above
contaminants at varying rates and efficiencies. The table below (Table 3) details the different purification
technologies and the ability of each to remove specific contaminants and whether they are excellent,
good or poor at removing that contaminant.
• Total solids
• Microbial
Table 2: Major classes of contaminants in water.
E = Excellent (capable of
complete or near total
removal)
G = Good (capable of removing
large percentages)
P = Poor (little or no removal)
Dissolved
Ionized
Solids
Dissolved
Ionized
Gases
Dissolved
Organics
Particulates Bacteria/
Algae
Pyrogens/
Endotoxins/
Viruses
Purification Process
Distillation E G/E (1) E E E E
Deionization (EDI) E E P P P P
Reverse Osmosis G (2) P G E E E
Carbon Adsorption P P (3) E/G (4) P P P
Micron Filtration P P P E P P
Sub Micron Filtration P P P E E P
Ultrafiltration P P G (5) E E E
U.V. Oxidation P P E/G (6) P G (7) P
(1) The resistivity of the water is dependent on the absorption of CO2.
(2) The concentration is dependent on the original concentration in the feedwater.
(3) Activated carbon will remove chlorine by adsorption.
(4) When used in combination with other purification processes special grades of carbon exhibit excellent capabilities for removing
organic contaminants.
(5) Ultrafilters, being molecular sieves, have demonstrated usefulness in reducing specific feedwater organic contaminants based on
the rated molecular weight cut-off of the membrane.
(6) 185 nm UV oxidation has been shown to be effective in removing trace organic contaminants when used post-treatment.
(7) 254 nm UV sterilizers, while not physically removing bacteria, have bactericidal or bacteriostatic capabilities limited by intensity,
contact time and flow rate.
• Particulates
• Organics
5. 5Compliance by Design METTLER TOLEDO
2.2 Pharmacopeia requirements for source water
The production of water for pharmaceutical use requires the source water used for purification to be
“water safe for human consumption as deemed by a competent authority”.
Source water requirements by pharmacopeia:
• USP: “It is prepared from water complying with the U.S. Environmental Protection Agency National
Primary Drinking Water Regulations or with the drinking water regulations of the European Union,
Japan, or with the World Health Organization’s Guidelines for Drinking Water Quality.”
• EP: “…from water that complies with the regulations on water intended for human consumption laid
down by the competent authority.”
• JP: “prepared from Water.”
• ChP: “prepared from water complying with National Standard of the People’s Republic of China.”
• IP: “…prepared from water meeting all statutory requirements for drinking water.”
3. Production Requirements for Bulk Waters
In addition to the water types as discussed above, bulk waters (PW, HPW, WFI) are the primary starting
point for all other waters. A facility must determine the type of bulk water they require and design the
system such that it will be compliant at all times. To ensure continuous compliance, the performance of
a pharmaceutical water purification, storage, and distribution system must be monitored.
The type of bulk water being produced determines the purification technologies that should be
incorporated into a system. For PW the system can incorporate any combination of technologies, but
specific water quality requirements must be met. For example, WFI should use distillation as the final
purification step. The one exception is for WFI for use in Japan only, where a combination of reverse
osmosis and ultrafiltration when fed PW can be the final purification step. HPW is a Europe only water
type which can be used for very limited pharmaceutical applications.
3.1 Basic water system monitoring requirements
• Monitoring of water sources regularly
- chemical and microbiological
- endotoxin (pyrogen) level where relevant
• Monitoring of system performance, storage, and distribution systems
• Records of results, and any actions taken
• Validated sanitization procedures followed on a routine basis
The storage and distribution system should be considered as a key part of the whole system, and must
be designed to be fully integrated with the water purification modules of the system. Once water has
been purified using an appropriate method, it can either be used directly or transferred into a storage
vessel for subsequent distribution to points of use. The storage and distribution system should be
configured to prevent recontamination of the water after treatment and be subjected to a combination of
on-line and off-line monitoring to ensure that the water is suitable for intended use and that the quality is
maintained. The final validation and the ongoing control of the water system must include all aspects of
the process, but special attention must be paid to the purification and storage and distribution sections.
PharmaceuticalWaterSystems
6. 6 METTLER TOLEDO Compliance by Design
3.2 Purified Water (PW) - USP37 – NF32
PW is water obtained by a suitable process. It is prepared from water complying with the U.S.
Environmental Protection Agency National Primary Drinking Water Regulations or with the drinking water
regulations of the European Union or of Japan, or with the World Health Organization’s Guidelines for
Drinking Water Quality. It contains no added substance.
3.3 Water for Injection (WFI) – USP37 – NF32
WFI is characterized by superior distillation in the removal of chemicals and microorganisms. It is
prepared from water complying with the U.S. Environmental Protection Agency National Primary Drinking
Water Regulations or with the drinking water regulations of the European Union or of Japan or with the
World Health Organization’s Guidelines for Drinking Water Quality. It contains no added substance.
PharmaceuticalWaterSystems
Attribute USP EP JP ChP IP
Source Water for PW
and WFI
US, EU, Japan,
WHO drinking
water
Human
consumption
JP water
specification
Potable water
or
Purified Water
Potable water
or
Purified Water
PURIFIED WATER
Production Method Suitable
process
Suitable
process
Distillation,
ion-exchange,
UF, or
combination
Distillation, ion-
exchange, or
suitable
process
Distillation, ion-
exchange, or
suitable
process
Total Aerobic (microbial)
(cfu/mL)
100 100 100 100 100
Conductivity
(μS/cm at 25°C)
1.3 (3 stage) 5.1 (1 stage) 1.3 on-line or
2.1 off-line
5.1 (1 stage) 1.3 (3 stage)
TOC (mg/L) 0.5 0.5 (optional) 0.5 (0.3 for
control)
0.5 0.5
Nitrates (ppm) 0.2 0.2 Required
Acidity/Alkalinity Required
Ammonium (ppm) 0.2 Required
Oxidizable Substances Required
WATER FOR INJECTION
Production Method Distillation or
suitable
process
Distillation
or RO with
additional
technology
Distillation or
RO with UF,
from Purified
Water
Distillation Distillation
Total Aerobic (microbial)
(cfu/100 mL)
10 10 10 10 10
Conductivity
(μS/cm at 25°C)
1.3 (3 stage) 1.3 (3 stage) 1.3 on-line or
2.1 off-line
1.3 (3 stage) 1.3 (3 stage)
TOC (mg/L) 0.5 0.5 0.5 (0.3 for
control)
0.5 0.5
Bacterial Endotoxins
(EU/mL)
0.25 0.25 0.25 0.25 0.25
Nitrates (ppm) 0.2 0.2 Required
Heavy Metals Required
Acidity/Alkalinity Required
Ammonium (ppm) 0.2
* Shaded boxes – no test required
Table 3: Requirements for bulk Purified Water and Water for Injection by pharmacopeia.
7. 7Compliance by Design METTLER TOLEDO 7
4. Biofilm
Free-swimming aquatic bacteria use polymucosaccharides as a glue to colonize surfaces and form a
biofilm. Biofilm is composed of cellular debris, organic material and a small number of vegetative cells.
Complex communities evolve which, when mature, shed micro-colonies and bacteria. This gives rise to
sporadic high counts in bacteria levels. The major groups of water borne contaminants are algae,
protozoa and bacteria.
Water treatment equipment, storage, and distribution systems used for PW, HPW and WFI should be
provided with features to control the proliferation of microbiological organisms during normal use, and
incorporate techniques for sanitizing or sterilizing the system after intervention for maintenance or
modification. The techniques employed should be considered during the design of the system and their
performance proven during the commissioning and qualification activities.
5. Designing and Engineering Pharmaceutical
Water Systems
A pharmaceutical water system that it is in compliance at all times and produces the intended quality of
water, should be properly monitored and controlled with a variety of parameters and instruments. When
planning the system, breaking it into three sections – pre-treatment, purification, storage and distribution
– simplifies the design process and will allow the system to be engineered to meet the facility’s demands.
5.1 Pre-treatment
The source water is a significant determining factor in what pre-treatment technologies will be utilized.
While the pharmacopeia requires, at a minimum, that the source water be safe for human consumption,
the ionic and organic profile of that water will vary depending on the source used, ground water or
surface water. This should be known and taken into consideration when deciding on the pre-treatment
system. A typical pre-treatment system incorporating several removal technologies and the parameters
that should be incorporated into the system to monitor performance and contaminant removal is shown
in (Figure 2).
PharmaceuticalWaterSystems
1. Pre-treatment
2. Purification 3. Storag
Multi-media
Filter
RO Unit Ultra Filtration
Unit
Electrodeionization
(EDI)
UV
Softener GAC
UV
Cartridge
Filter
(1-5µ)
Break
Tank
PW or HPW
Feed
Water
Water
divide
1. Pre-tr
2. Purifi
3. Stora
C
C
C
C
C C
TOC
pH
C pH
pH
RMS
Figure 2: Schematic of pre-treatment system.
Measurement Points ConductivityC TOC TOCTOC pHpH
pHpHMeasurement Points ConductivityC
8. 8 METTLER TOLEDO Compliance by Design
This system includes filtration (multi-media and cartridge filters), softener (to reduce hardness), Granular
Activated Carbon (GAC - for organic removal) followed by additional filtration at a smaller micron rating, UV
treatment (for inactivation of microbial contaminants) and then the addition of acid, alkali or sodium bisulfite
to adjust the pH and remove chlorine.
Many of the pre-treatment processes involve the physical removal of contaminants so monitoring will utilize
pressure and flow to determine maintenance and replacement schedules. Further in the pre-treatment module,
pH and ORP are the controlling parameters for the adjustment of pH and determining the removal of chlorine
or other oxidants.
5.2 Purification
The purification section will vary depending on the water type being produced for the specific pharmaceutical
applications and the capacity required, plus any future expansion requirements. In general, if the intention is
to produce WFI the purification will include reverse osmosis and either deionization or electrodeionization
followed by distillation. The inclusion of UV oxidation is for inactivation of bacteria, and in some systems there
may be ultrafiltration, but it would only be installed before the last purification process. Filtration after the
water has been treated is strongly discouraged by the regulators as it may be a potential site for microbial
growth.
The entire purification process is shown with the parameters that should be incorporated in the system (Figure
3). The purification process is the part of the pharmaceutical water system that determines the quality of the
water and the type of water that is being produced. This is also an area of a pharmaceutical facility that will
be audited by regulators and inspectors (the water system is one of the most audited aspects of a
pharmaceutical facility).
The measurement parameters utilized in the purification process are not only used to control the performance
of the system, but are also the measurements that must be reported to confirm the quality of the water being
produced. Control and system monitoring of the process will or should include; flow, pressure, temperature,
bioburden, pH and ORP. However, these parameters are not part of the required tests for the pharmacopeia,
but they are critical to the proper control of the purification system. In addition, there will be conductivity and
TOC measurements installed on the system, not only for control and monitoring, but also as regulatory control
PharmaceuticalWaterSystems
Figure 3: Schematic of entire purification system.
1. Pre-treatment
2. Purification 3. Storage a
Multi-media
Filter
RO Unit Ultra Filtration
Unit
Electrodeionization
(EDI)
UV
Softener GAC
UV
Cartridge
Filter
(1-5µ)
Break
Tank
Distillation
for WFI
PW or HPW
Storag
Tank
Feed
Water
Water tre
divided in
1. Pre-treatm
2. Purificatio
3. Storage a
C
C
C
C
C C
C TOC
TOC
Measurement Points ConductivityC TOC TOCTOC pHpH
pH
C pH
pH
RMS Bioburden
RMS
Measurement Points ConductivityC TOC TOCTOC pHpH
pHpH
Measurement Points ConductivityC TOC TOCTOC pHpH ORPORP PressureP
Measurement Points ConductivityC
9. 9Compliance by Design METTLER TOLEDO
points. For WFI and PW there are conductivity, TOC and microbial contamination limits that must be
monitored and reported. While off-line testing is still permitted, the pharmacopeias are encouraging the
use of on-line testing and cautioning that off-line testing can be a source of false test results.
“Online conductivity testing provides real-time measurements and opportunities for real-time
process control, decision, and intervention. Precaution should be taken while collecting water
samples for off-line conductivity measurements. The sample may be affected by the sampling
method, the sampling container, and environmental factors such as ambient carbon dioxide
concentration and organic vapors.”
USP 645
The pharmacopeias require that the conductivity, TOC and microbial contamination be tested and
reported from a point that demonstrates the quality of water used in production. This reporting point is
usually after the last point-of-use.
5.3 Storage and distribution
The storage and distribution section must take into consideration the on-demand requirements for water,
the peak demand, sanitization and distribution piping. Shown below is a system layout for storage and
distribution with the parameters that should be included as part of the system design.
Measurement parameters that must be included in the storage and distribution section are flow, pressure
and temperature. In addition, conductivity, TOC and microbial contamination are also included because
these are the reportable measurements to determine if the water quality meets the requirements for PW
or WFI. If the storage and distribution system utilizes ozone for sanitization then the loop will require
multiple ozone measurements to verify ozone destruction and therefore comply with the “no added
substance” requirement.
Piping, tanks, tank liners, and all materials of construction – including fittings, pumps and valves are all
in direct contact with pharmaceutical waters and all are potential risks for degradation of the purified
water. Therefore, these water system components must be selected carefully to ensure that they are
sanitary in nature and that none will leach any potential contaminants into the water, degrading water
quality and risking compliance.
PharmaceuticalWaterSystems
Figure 4: Schematic of storage and distribution system.
Storage
Tank
UV
O3
Ozone
Generator
Heat
Exchanger
Treated Water Supply
Points
of
Use
1. Determine O3
concentration in storage tank.
2. Determine O3
concentration is “zero” after ozone destruct loop during production.
O3
O3
TOC
TOCC O3
C
3. Storage and Distribution
Measurement Points ConductivityC O3 Dissolved OzoneTOC TOCTOC
RMS
RMS
RMS Bioburden
The multi-parameter
M800
10. 10 METTLER TOLEDO Compliance by Design
Suitable materials include:
• stainless steel Grade 316 L (low carbon)
• polypropylene (PP)
• polyvinylidenedifluoride (PVDF)
• perfluoroalkoxy (PFA)
• unplasticized polyvinylchloride (uPVC) used for non-hygienic designed water treatment equipment
such as ion exchangers and softeners
6. Instrumentation Recommendations for
Pharmaceutical Water Systems
For every section of the water system there are three measurement types that are monitored and controlled,
which are: chemical, physical and biological.
The control of each section of the water system depends on the inclusion of the proper controls for every
area of purification. Additional measurements will not produce better water but will give better control and
monitoring. Shown below in Table 6 are the measurement parameters for a water system which provides
some monitoring guidelines for different purification technologies.
Unit Process
Parameters
Cond/
Res
Temp Bioburden TOC pH/
ORP
O3 Press Level Flow
Media Filters, Depth and
Sand Filters
• • • •
Softeners • • • •
Carbon (GAC) Filters • • • •
pH Adjust (Acid/Caustic
Injection) *PID Control
• *
Reverse Osmosis • • • • • •
Ion-Exchange (Mixed-Bed) • • • •
Electrodeionization • • • •
Distillation • • •
Ozone (injection,
destruction, sanitization)
•
Storage Tank • • • • •
Distribution Loop • • • • • • •
Table 4: Overview of recommended parameters for different unit processes.
PharmaceuticalWaterSystems
11. 11Compliance by Design METTLER TOLEDO
METTLER TOLEDO Thornton Solutions
Our wide range of analyzers, sensors and transmitters monitor your Pharma Waters systems to ensure
they are always compliant with pharmacopeia requirements.
PharmaceuticalWaterSystems
7000RMS Microbial
Detection Analyzer
• Real-time detection of microbial contamination
• Detection limit of one auto fluorescent unit (AFU)
• No sample preparation, staining or reagents
required
• User-defined alarm and alert thresholds
• No moving parts and automatic sanitizing
function
Don’t miss a bug with continuous, on-line
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5000TOCi Analyzer
• Complete process control and precise data
trending
• Plug and Measure functionality
• Instant notification of excursion
• Simplified record keeping for SST and CAL
• Trouble-free maintenance
• Robust, reliable design virtually free from
moving parts
• Compliant with all pharmacopeias
Delivering the power of an analyzer with the
convenience of a sensor.
Portable 450TOC
Analyzer
• Portable, fast response technology for rapid
detection
• Continuous measurement for superior
system profiling and performance trending
• On-board data logging to USB memory stick
• USB printer support for hard-copy record
keeping
• Compliant with USP, EP, Ch P and JP
Providing convenient, on-the-spot TOC and
conductivity analysis.
UniCond®
Conductivity
Sensors
• Conductivity Factory Calibration data stored
internally in sensor
• Plug and Measure functionality
• Integral high-performance measuring circuit
• Robust digital output signal
• Complete calibration for pharmaceutical
compliance
Calibration tracked by iMonitor (M800) to
ensure compliance.
pureO3
TM
Sensor
• Rapid, accurate response
• Easy maintenance with drop-in membrane
• Plug and Measure functionality
• Positive zero detection
• Assured compliance with “no added
substance” rule
Confidently monitor complete sanitization
and confirm ozone destruction.
M800 M300
Transmitters
• Multi-channel (2 or 4) transmitter with
multi-parameter measurement flexibility
• Plug and Measure simplicity
• Measurements are available within seconds
of connection
• Meets all pharmacopeias’ requirements for
calibration
Simple menu operation with unparalleled
performance and accuracy.