Design of Purified water & WFI Systems

Water is the one of the major commodities used by the pharmaceutical industry. It is widely used as a raw material, ingredient, and solvent in the processing, formulation, and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, and analytical reagents. It may present as an excipient, or used for reconstitution of products, during synthesis, during production of finished product, or as a cleaning agent for rinsing vessels, equipment and primary packing materials etc.

There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life.

There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and other quality attributes.

Different grades of water quality are required depending on the different pharmaceutical uses.

Types of Water used:

Water is the most common aqueous vehicle used in pharmaceuticals. There are several types of water are used in the preparation of drug product, such as:

  1. Non potable water: It is water that is not of drinking water quality, but which may still be used for many other purposes, depending on its quality. It is generally all raw water that is untreated, such as that from lakes, rivers, ground water, springs and ground wells.
    Purposes:

    • cleaning of outer surface of the factory
    • used in garden
    • washing vehicles etc.
  2. Potable water: It is not suitable for general pharmaceutical use because of the considerable amount of dissolved solids present. These consist chiefly of the chlorides, sulphates & bicarbonates of Na, K, Ca and Mg. A 100 ml portion of water contains not more than 100 mg of residue (0.1%) after evaporation to dryness on a steam bath.
    Purposes:

    • To use as drinking water
    • Washing & extraction of crude drugs
    • Preparation of products for external use
  3. Purified water: It is used in the preparation of all medication containing water except ampoules, injections, some official external preparations such as liniments. It must meet the requirements for ionic & organic chemical purity & must be protected from microbial contamination.
    Purposes:

    • For the Production of non-parenteral preparation/formulation
    • For the Cleaning of certain equipment used in non-parenteral product preparation
    • For Cleaning of non-parenteral product-contact components
    • For All types of tests
    • For the Preparation of some bulk chemicals
    • For the preparation of media in microbiology

Water for Injection (WFI):

Water for Injection is a solvent used in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications.(WFI) is sterile, non pyrogenic, distilled water for the preparation of products for parenteral use.

It contains no added substance and meets all the requirements of the tests for purified water. It must meet the requirements of the pyrogen test. The finished water must meet all of the chemical requirements for Purified Water as well as an additional bacterial endotoxin specification.

Since endotoxins are produced by the kinds of microorganisms that are prone to inhabit water, the equipment and procedures used by the system to purify, store, and distribute Water for Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxins from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.

Purposes:

  • For the production of parenteral products/formulation
  • For cleaning of parenteral product-contact components

Preparation technique:

  • Distillation
  • Reverse osmosis
  • Membrane process

Storage condition:

It can be stored for periods up to a month in special tanks containing ultraviolet lamps. When this freshly prepared water is stored and sterilized in hermitically sealed containers, it will remain in good condition indefinitely.

If autoclave is not available, freshly distilled water may be sterilized by boiling the water for at least 60 minutes in a flask stoppered with a plug of purified non-absorbent cotton covered with gauze, tin-foil or stout non-absorbent paper; or the neck of the flask may be covered with cellophane and tightly fastened with cord.

WFI System validation process:

How to preform WFI system validation in Pharmaceuticals and Acceptance Criteria for Water for Injection.

Process:

  1. Perform Installation Qualification. Verify piping, fittings, proper dimensions drawings, wiring, PC software, calibration, and quality of materials.
  2. Check flow rates, low volume of water supply, excessive pressure drop, resistivity drops below set point, and temperature drop or increase beyond set level.
  3. Perform general operational controls verification testing.
  4. Operate system throughout the range of operating design specifications or range of intended use.
  5. System regulators must operate within ±2 psi of design level.
  6. Operate the system per SOP for operation and maintenance of purified water system. Perform sampling over a 1 month period per the sampling procedure and schedule.
    Test samples for conformance to current USP Water for Injection monograph, microbial content and endotoxin content. Identify all morphological distinct colony forming units (CFUs) to at least the genus level
  7. Measure the flow rate and calculate the velocity of the water, or measure the velocity directly at a point between the last use point and the storage tank.
  8. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualification testing.

Acceptance Criteria

  1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
  2. General controls and alarms operate in accordance with design specification.
  3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
  4. The system flow rate must be in compliance with design specifications.
  5. All samples must meet the following criteria:
    1. Chemical Testing: Test samples must meet the acceptance criteria of the chemical tests as described in USP Monograph on Water for Injection.
    2. Bacteriological Purity: All samples must contain no more than 10 cfu/100 ml; no pseudomonas or coliform are detected.
    3. Endotoxins: All samples must contain no more than 0.25 EU/ml.
    4. Physical Properties: The temperature of the hot Water for Injection must be greater than 80°C.
    5. Particulate Matter: Small Volume Injection: The Small Volume Injection meets the requirements of the test if the average number of particles it contains is not more than 10,000 per container that are equal to or greater than 10 µm in effective spherical diameter and not more than 1000 per container equal to or greater than 25 µm in effective spherical diameter.

If you require technical assistance regarding purified water & WFI systems please feel free to contact on +91-22-66735960 or use our technical support form.

FDA’s role in plant design

If you are involved in any type of manufacturing that is regulated by the FDA, FDA regulatory consulting firms can help you!

FDA consultants (who are all former employees of the FDA or have extensive industry experience) can assist with all phases of the manufacturing process, from single rooms to entire plants, computer systems to manufacturing and processing equipment, design to verifications and validations.

FDA consulting and FDA training services typically include:

  • master and batch record design and reviews
  • specification development (components, in-process, and finished product)
  • supplier audits
  • medical device design history file (21 CFR 820.30)
  • dietary supplements product design
  • equipment verification
  • process validation (prospective validation, retrospective validation, and revalidation)
    • DQ (Design Qualification)
    • IQ (Installation Qualification)
    • OQ (Operational Qualification)
    • PQ (Prospective Qualification)
  • cleaning validation (all industries)
  • GMP (Good Manufacturing Practices) and HACCP (Hazard Analysis and Critical Points)
  • stability studies
  • clean rooms
  • sterility
  • calibration
  • PM (Preventive Maintenance) and DM (Demand Maintenance)
  • plant design
  • computer system development and validation
    • ERP software (Enterprise Resource Planning)
    • data collection and storage systems
    • production equipment
    • system software for manufactured products


FDA’s role in plant design:

  1. cGMP requirements

    1. Design & Construction features
    2. Lighting
    3. Ventilation, air filtration, air heating and cooling
    4. Plumbing
    5. Sewage & refuse
    6. Washing & Toilet facilities
    7. Sanitation
    8. Maintenance

 

  1. cGMP Coverage of design
    FDA’s Compliance Programs provide instructions to FDA personnel for conducting activities to evaluate industry compliance with the Federal Food, Drug, and Cosmetic Act and other laws administered by FDA. Compliance Programs are made available to the public under the Freedom of Information Act.
    Compliance Programs do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used as long as the approach satisfies the requirements of the applicable statutes and regulations. FDA’s Compliance Programs are organized by the following program areas:

    • Biologics (CBER)
    • Bioresearch Monitoring (BIMO)
    • Devices/Radiological Health (CDRH)
    • Drugs (CDER)
    • Food and Cosmetics (CFSAN)
    • Veterinary Medicine (CVM)

 

  1. Facilities & Equipment Systems
    • Cleaning & maintenance
    • Facility layout and air handling systems for prevention of cross-contamination (e.g. Penicillin, beta-lactams, steroids, hormones, cytotoxics, etc.)
    • Specifically designed areas for the manufacturing operations performed by the firm to prevent contamination or mix-ups
    • General air handling systems
    • Control system for implementing changes in the building
    • Lighting, potable water, washing and toilet facilities, sewage and refuse disposal
    • Sanitation of the building, use of rodenticides, fungicides, insecticides, cleaning and
    • Sanitizing agents

 

  1. Preapproval Coverage of Design/Preapproval Inspections/Investigations
    The addition of any new drug to a production environment must be carefully evaluated as to its impact on other products already under production and changes that will be necessary to the building and facility. Construction of new walls, installation of new equipment, and other significant changes must be evaluated for their impact on the overall compliance with GMP requirements.
    For example, new products, such as cephalosporins, would require that the firm demonstrate through appropriate separation and controls that cross-contamination cannot occur with regard to other products being made in the same facility. Also, facilities that may already be operating at full capacity may not have adequate space for additional products


Quality Systems Approach to Pharmaceutical cGMP Regulations

Quality by design means designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process.

Quality by design, in conjunction with a quality system, provides a sound framework for the transfer of product knowledge and process understanding from drug development to the commercial manufacturing processes and for post-development changes and optimization.

The CGMP regulations, when viewed in their entirety, incorporate the concept of quality by design. This guidance describes how these elements fit together.

For more information on FDA consulting services for plant design or to schedule a consultation, please contact us.