Water for Pharmaceutical Use

1.0 Introduction

1.1 Scope – The document provides the guidance about the specifications of water for pharmaceutical use in accordance to its quality for the manufacture of APIs and dosage forms in accordance with the Good Manufacturing Practices (GMP).

1.2 General Principles

The water for pharmaceutical production, storage and distribution should be designed, installed, commissioned, qualified, and maintained to ensure the water produced is of appropriate quality.

Validation of water should be done to ensure it is stored, distributed and generated in compliance with the specifications

The system capacity should be designed to meet the average peak flow demand of present operation or to permit modification if necessary.

All systems should have apt recirculation and turnover to ensure it controlled microbiologically and chemically.

After validation or maintenance or modification work the system should be approved by the quality department for its usage by change control documentation.

The sources of water should be checked regularly for microbiological, chemical and endotoxin contamination.

A validated procedure should be followed for chemical sanitization of water systems which is an integral part of bio contamination programme.  

1.3 Quality specifications

1.3.1 General

The specifications for bulk and dosage forms are given by the pharmacopoeias.

Various limits for impurities or class of impurities are given.

1.3.2 Drinking water

It should be supplied under continuous pressure in plumbing system which is free from defects which may cause contamination of product.

Drinking water is not modified except for the limited treatment of water from stored or natural source. Treatment is done by desalinization, softening, removing specific ions, reduction of particles and anti-microbial treatment.

Drinking water from public water supply may be a combination of more than one natural source or supplied from offsite source like municipality but the quality should be maintained by suitable processing.

The water may be treated to achieve drinking water quality first and later purified water. Here drinking water quality is achieved by identifying and testing.

If the water is used in manufacturing then it should be periodically tested.

1.3.3 Bulk purified water

It is prepared from drinking water source as minimum quality feed water.

It should achieve the specifications given for chemical and microbiological purity and should be protected against contamination

It is prepared by reverse osmosis, electro deionization and vapor compression.

Alert levels are not given by pharmacopoeias and are determined by knowledge of the system

1.3.4 Bulk highly purified water

It is prepared from drinking water source as minimum quality feed water.

Its specification is given by European pharmacopoeia.

Its quality standards, limits, microbiological requirements should be similar to WFI.

Production methods include double pass RO coupled with other techniques like deionization and ultrafiltration.

It should be protected from contamination and microbiological proliferation.

1.3.5 Bulk water for Injections

It is prepared from drinking water source as minimum quality feed water.

It is an intermediate bulk product and is used as an ingredient for formulation.

It is the highest quality of pharmacopoeial WPU.

It should achieve the specifications given for chemical and microbiological purity and should be protected against contamination and microbiological proliferation.

1.4 Water purification systems

1.4.1 General  

The specifications for WPU in pharmacopoeias don’t give the permissible water purification methods apart from BWFI

The water treatment method should include the following

•  Final water quality specifications
• Quantity of water required by the user
• Available feed water quality and the variation observed over time
• Availability of suitable support facilities for system connection like raw water, electricity, exhaust and compressed air
• Sanitization strategy
• Availability of water treatment equipment on the market
• Reliability and robustness of water treatment equipment
• Efficiency or yield of purification system
• Ability to support and maintain water purification equipment
• Operational usage – hours/days, days/years and planned downtime
• Total life cycle costs

The specifications for water purification equipment, storage and distribution systems should include the following

• Location of plant room
• Temperature fluctuations that system can encounter
• Risk of contamination from contact materials
• Hygienic or sanitary design
• Corrosion resistance
•  Leakage
• Tolerance to cleaning and sanitizing agents
• Sanitization strategy
• System capacity and output requirements
• Instruments, test and sampling points provision

The design, layout and configuration of water purification equipment, storage and distribution systems should include the following physical considerations

•  Sample collection ability
• Installation space available
• Structural loadings on buildings
• Provision of adequate access for maintenance
• Ability to handle regeneration and sanitization chemicals

1.5.1 Production of drinking water

Drinking water is derived from raw water source like well, river or reservoir. No prescribed methods are given for treatment of raw water to drinking water

Processes employed by water supply authority

• Desalinization
• Filtration
• Softening
• Disinfection/ sanitization
• Ferrous / iron removal
• Precipitation
• Reduction of inorganic or organic materials

The quality of the water should be monitored regularly and testing should be done when there is change in raw water source.

Changes can be reviewed by trend review

Changes can’t be made until it is approved by the QA department

The configuration of the storage system should be documented

Drinking water is usually considered to be “indirect impact system” and need not be qualified

Vendor assessment, authorized certifications, confirmation of acceptability of delivery vehicle should be done.

Equipments, systems, storage tanks should be with protected vents and allow for visual inspection for being drained and sanitized.

Contamination controlling techniques like back flushing, chemical or thermal sanitization and frequent regeneration should be considered appropriate

1.5.2 Production of purified water

Any qualified purification technique can be used to prepare purified water. It is produced by ion exchange, RO, ultrafiltration, distillation and electro deionization processes

User requirement specifications to be followed

• Feed-water quality and its variation over seasons
• Quantity of water required by the user
• Water-quality specification
• Sequence of purification stages required
• Energy consumption
• Extent of pretreatment required to protect the final purification steps
• Performance optimization, including yield and efficiency of unit treatment-process steps;
• Appropriately located sampling points designed in such a way as to avoid potential contamination
• Unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.

Ambient temperature systems like ion exchange, RO and ultrafiltration are susceptible to contamination when equipment is static.

Documented evidence should be provided for efficacy

The following should be considered

• Minimum flow should be maintained for water generation system at all times
• Temperature should be controlled by heat exchanger or plant room cooling to reduce microbial growth
• Provision for ultraviolet disinfection
• Water treatment components should be sanitized periodically         

1.5.3 Production of highly purified water

It can be produced by double pass reverse osmosis coupled with ultrafiltration or any other qualified purification technique

1.5.4 Production of water for injection

Some pharmacopoeias prescribe or limit the permitted final water purification stage in the production of BWFI

Distillation is the preferred technique based on phase change and high temperature operation of process equipment

Following should be considered in designing water purification system and defining URS

• Feed water quality
• Water quality specification
• Quantity of water
• Blow down and dump functions
• Cool down venting to avoid contamination ingress
• Optimum generator size or generators with variable control to avoid over frequent start/stop cycling

1.6 Water storage and distribution system

The storage and distribution system should be considered as a key part of the whole system and should be designed to be fully integrated with the water purification components of the system. Water is one of the major commodities used by the pharmaceutical industry. It may be present as an excipient or used for reconstitution of the products during synthesis, production of the finished product or as cleaning agent for rinsing vessels, equipment, primary packaging materials etc. once water for pharmaceutical use has been obtained, it must be stored and distributed to the points of use, there is no point in producing quality water unless it is correctly stored and distributed. This stage is of vital importance to minimize possible contamination of the water and the proliferation of micro-organisms. Systems must be sealed with continuous recirculation and must have sanitization systems. In this work the first stage is to automate the water storage & distribution for various requirements and control the level in the storage tank and monitoring the PH, conductivity, temperature before distribution which is very important as any small change in these parameters may hinder the performance of the whole pharmaceutical plant. The next stage of the work is to control the flow rate of the water in the distribution line and then water is given to the UV treatment to minimize contamination and micro-organisms.

The materials that come into contact with water for pharmaceutical use, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.

• Compatibility - The compatibility and suitability of the materials should encompass the full range of its working temperature and potential chemicals that will come into contact with the system at rest, in operation and during sanitization.
• Prevention of leaching - All materials that come into contact with water in pharmaceutical plant should be non-leaching at the range of working and sanitization, temperatures of the system.
• Corrosion resistance - Water used in pharmaceutical plant are highly corrosive.

1.7 Microbiological test for water

The microbiological and chemical testing for Water used in pharmaceutical plant, Conductivity testing establishes a sample’s ability to conduct electricity, which relates to the number of dissolved salts (ions) in the sample, high ion count lowers water purity and may indicate a processing problem. Total organic compounds (TOC) testing finds whether carbons in the sample are maintained below a mandated limit of 500 parts per billion (ppb), high is a reliable indicator of sample contamination.

Bioburden testing establishes the number of microorganisms in a water sample, ensuring bacterial loads don’t exceed mandated USP levels.

These criteria required testing for the following.

• Bacteria Escherichia coli (E. coli), Staphylococcus auseus (S. auseus), Pseudomonas aeruginosa (Ps. Aeruginosa)
• Fungus Aspergillus niger (A. niger)

Microbial test of water includes the estimation of the number of viable aerobic bacteria present in a given quality of water.

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