The biopharmaceutical industry and the semiconductor industry have a few things in common. One is that the investor community
regards both as high technology. Another is that manufacturing relies upon water of extreme purity.1 There are lessons to be learned from the experience of the semiconductor industry, as it has long practiced matching multiple
purity levels to appropriate tasks.
The biopharmaceutical industry has been guilty of using the simple, but expensive, route of using Water for Injection (WFI)
everywhere. Because water is highly scrutinized by regulatory agencies, it seems easier to overreact and overdesign according
to a superstitious view of these regulations.
GOOD PLANNERS WIN
While there are many ways to reduce the costs of high-purity water systems, the principal one is proper planning. Water is
often considered to be another unimportant utility when constructing a new facility or renovating an existing facility. There
is probably more planning for the electrical distribution system than the water system. If the designers actually looked at
the energy budget associated with technical water processing, distribution, and utilization, they would find significant opportunities
for savings. We suggest drawing up a water master plan at a level of detail similar to a validation master plan. It should
be done at the same time as the validation master plan.
The major results from planning are:
- improved product water quality
- reduced capital investment
- reduced maintenance and operational costs
- water conservation.
The water master plan should include:
- an introduction and overview of the facility water, listing each water user with volume and purity
- identification of the water source, including analytical data
- a plan or drawings showing the location of each system
- descriptions and drawings of each system
- identification of the individual systems with a tag number or code
- distribution charts — including piping sizing, construction materials, and any other pertinent data
- water usage for each operation or building (for a new facility, this will be a projection)
- specifications for different water types
- designated applications for each type of water within the building
- initial engineering documentation for each system (user requirement specifications and enhanced design review)
- capital cost estimates
- operating cost estimates for each type of water.
An expert will be needed to prepare this water master plan. If it is for a new facility, the best time is at the conceptual
design phase of the project. Probably the best procedure is to hire an architectural and engineering (A&E) firm for the conceptual
design and the water master plan. However, most A&E companies have limited expertise in designing high-purity water systems,
so it is best to also hire a consultant with extensive experience to ensure that the A&E firm has considered all options.
This consultant should also conduct a completely independent appraisal of the master plan.
High-Purity Water in a Nutshell
THE FACILITY EXAMPLE
Here is a description of the water plan for a new grass-roots facility producing four different active pharmaceutical ingredients
(APIs) using a cell culture process. We introduce the workings of the plan with an example rather than indulging in generalities.
Overview of facility water
This facility consists of multiple buildings in a campus-like location. It mainly does production, with supporting laboratories
and administration. The water is from a municipal source. The facility has its own waste treatment facility.
The types of water to be used in this facility are:
- non-potable water (for fire protection and process)
- potable (drinking) water
- water for sanitary facilities
- compendial water (including USP-purified water, WFI, and clean steam)
The water systems in the facility include:
- cooling towers
- boiler feed
- fire protection
- facility wash-down and cleaning
- drinking water
- waste treatment
- biopharmaceutical manufacturing
- animal drinking water
- fill and finish.
Make a page for the water from the municipal source. This water must meet EPA drinking water specifications. This information
becomes part of the design basis of the treatment options. The municipal EPA quality report, which should be on file, supplies
documentation of all trace constituents. Learn about EPA regulations at
Examine the distribution system and determine the waste treatment quantities and their sources. The best approach is to prepare
an extensive spreadsheet listing each user and the quantities of water required. This translates into a material balance for
the entire plant.
A water distribution plan is at the heart of an overall energy and water conservation program. All water entering the facility
receives an initial pretreatment of multi-media filtration and softening. Although this adds cost to the overall plan, the
advantages are less maintenance and longer life for downstream equipment.
The second unique feature revolves around the reverse osmosis (RO) block. Using RO water for the boiler feed can significantly
reduce the amount of chemical additives and maintenance required, as compared to untreated water. Also, RO water can be used
for drinking water for personnel and animals.
The most important water conservation area is the RO reject stream (the retentate). This is frequently sent to the sewer,
but it can be made into a useful product by proper operation of the RO unit. A high rejection rate results in a fairly concentrated
retentate, which makes it unsuitable for reuse. Running the RO at 50% conversion (product/reject ratio) produces good quality,
softened, filtered RO reject water. This RO reject water is better quality than the raw city water feed. Other advantages
of this RO rejection rate are higher RO product water quality, extended RO-membrane lifetime, and little, if any, membrane
cleaning. The high-quality retentate can be used for cooling tower makeup, vapor-compression still feed, and clean steam-generator
feed. (Care must be taken regarding the silica content, which should not exceed 15 ppm for both still and generator feeds.)
According to ISPE, it is not cost effective to use only WFI in a biopharmaceutical facility.2 WFI is the most expensive water that can be produced but not the highest quality water that can be provided. Bjurstrom and
Coleman stated in 1987, "Water for Injection, the most expensive type of purified water, is generally used only when required
or when it is cost effective."3 The plan has determined the required quantities of water, as well as cost estimates in the production area.
FDA does not give much guidance on what types of water should be used for non-injectable purposes. On the other hand, the
European Agency for the Evaluation of Medicinal Products (EMEA) has published very extensive lists (five tables) of the minimum
acceptable quality of water for pharmaceutical and veterinary products.4 Tables 3 and 5 of Reference 3 describe the most important applications for APIs. Additional guidance can be obtained from
ISPE's Baseline Pharmaceutical Engineering Guide, Volume 4: Water and Steam Guide.
EMEA has designated a new grade of water named Highly Purified Water.4 The definition of this grade is that it is "intended for use in the preparation of products where water of high biological
quality is needed, except where Water for Injections is required. Current production methods include, for example, double-pass
reverse osmosis coupled with other suitable techniques such as ultrafiltration and deionization." This grade of water is not
yet recognized in the US, but it is the best choice for laboratories and sophisticated technical applications. Call it "purified
water" in regulatory documents.
Using WFI in the laboratory is not recommended. WFI contains metals leached from stainless steel piping that contribute to
measurable conductivity, although within USP requirements (Figure 1).5