Producing Affordable, High-Purity Water

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:

• sanitation

• cooling towers

• boiler feed

• fire protection

• humidification

• irrigation

• facility wash-down and cleaning

• cafeteria

• drinking water

• waste treatment

• biopharmaceutical manufacturing

• laboratory

• 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 www.epa.gov/safewater .

DISTRIBUTION SYSTEM

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.)

COMPENDIAL WATER

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.²

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

LABORATORY WATER

During the last five years, we have found that the technical requirements for laboratory water have tightened from "reagent grades" to match those of the semiconductor industry. The quality must meet the needs of sophisticated analytical methods and technologies. Figure 2 is a block process flow diagram of a recommended water system that will produce water of very low conductivity, low total organic carbon (TOC) and low microbial content.

Figure 1. The five orange-colored rows in the front are data taken from an essentially plastic system. The five blue-colored rows in the back are data taken from stainless steel systems.

MANUFACTURING

If you examine many manufacturing facilities, you will find a large variety of grades of water used in the various operations. The use of WFI when it is not needed is not cost effective, and it can also have a deleterious effect on the product, since it contains metals reflecting the composition of 316L Stainless Steel (Figure 1).

Table 1 is a water chart for a typical cell culture or microbial fermentation manufacturing operation. The left side shows the process and support operations, and the right shows the minimum recommended grade of water to be used in each step. Only three need WFI.

TABLE 1. RECOMMENDED WATER USAGE

PRODUCTION OF HIGH PURITY WATER

There are many ways to produce USP Purified Water and WFI. We design for USP Purified Water to meet Highly Purified Water quality specifications without incurring additional cost. Following Figure 2 from the beginning of the purification process, the following steps are recommended to produce USP Purified Water:

• a raw water totalizing flow meter

• a booster pump (if required)

• hot and cold mixing valve with temperature indicator to maintain constant temperature (optional)

• multi-media back-washable filter

• softeners

• carbon filter

• RO pre-filter(s)

• an RO system

• a storage tank (polyethylene or polypropylene)

• distribution pump(s)

• TOC reduction UV (185 nM)

• mixed beds (virgin ion exchange resin)

• final filter

• backpressure control valve

Proper design and operation of the system make it cost effective. It is a low maintenance system. In normal operation, no scheduled sanitization is required for any portion of the system (pretreatment, RO, or distribution). The carbon filter prevents excessive microbial levels in the effluent, although it does not eliminate bacteria. (That would be unrealistic.) Pretreatment microbiological levels, even from the carbon, should not exceed 200 colony forming units (cfu) per mL (which is better than drinking water).

Figure 2. Highly Purified Water System

The carbon filter serves two purposes. It removes chlorine, and it significantly reduces TOC. TOC is food for microbes, and its reduction prevents significant proliferation throughout the system, even in the product water. The carbon filter provides a long path for the water (for chloramine control) and performs proper back flushing (twice a week is recommended).

Using sodium metabisulfite is not recommended, since it has no effect on TOC and is associated with biofouling of RO membranes. A common misconception is that hot water or steam sanitization will decrease the microbial load in the carbon bed. It does, but only for a brief period. The carbon bed often shortly reverts back to too numerous to count (TNTC) levels due to the rapid recolonization of the sanitized biofilm in the carbon bed. Back flushing is far more effective. The pre-treatment steps can be kept under microbial control using these methods.

THE BUG STOPS HERE

The RO unit may be the most important step in the purification process. RO provides an impenetrable barrier to suspended solids and bacteria. In spite of the fact that no bacteria can get through the membrane or seals, some will be present in the RO product water. The microbiological numbers should be no more than 50 cfu/mL, which meets the USP Purified Water specification. Even with TNTC levels, the RO system reliably blocks the passage of microbes to the downstream sections of the water system. The RO product water is an ideal grade of water to be stored for processing to final higher quality as required.

There is usually some sort of error when a RO unit is not working right. In the pharmaceutical industry, RO units are often operated continuously in a mistaken attempt to control microbiological activity, or because they are paired with newer electrodeionization (EDI) units that require a continuous flow to maintain quality. Despite the use of a break tank to attempt to conserve water, high conversion rates must be employed to reduce the quantity of discarded water. These RO units are typically operated at 70-85% conversion, which is higher than that recommended by the membrane manufacturers, or as evaluated by the FilmTec ROSA (reverse osmosis system analysis) program.⁶ The highly concentrated reject water is also undesirable for reuse due to an excessive concentration of impurities.

The best fix almost always turns out to be to design and operate at 50% conversion (in other words, the same quantity of product as retentate). If the client wants to increase the percent conversion, we allow 5% increments after six months of trouble-free operation, up to 70% conversion. This eliminates RO membrane cleaning, increases reliability, and results in consistent product water quality. Also, the reject water is well suited for reuse.

POST-TREATMENT SYSTEM

In post-treatment (after storage), we actively destroy, remove, and prevent the inoculation and proliferation of microorganisms. Post-treatment provides an ultrahigh purity environment and a multi-step protection of the product water and its distribution loop. Two key steps in post-treatment are TOC reduction with ultraviolet radiation at a 185 nM wave length and deliberately avoiding regenerated mixed-bed resin, which is a primary source of microbiological contamination. The high energy UV radiation is a very effective barrier to all microorganisms. It destroys cells in several ways and denatures proteins and endotoxins. Virgin ion-exchange polisher-media (low TOC) will not add or support microbes. In order to prolong the life of the resin, we suggest that a nitrogen blanket be employed on the storage tank.

Figure 3. A water system was sampled at the return of the product water from distribution piping every week for a year. TOC never went over 5 ppb.

In both pre-treatment and, especially, post-treatment, controlling TOC leads to controlling microbial growth. Figures 3 and 4 show TOC and microbial data from the laboratory system over a period of one year. Controlling the TOC well below 20 ppb keeps the microbial level at or less than 1 cfu/mL. Obviously, this is well below the usual USP27 recommended action limits of 100 cfu/mL for purified water and 10 cfu/mL for WFI.

Figure 4. The water of this system was assayed by growing colonies. Six samples a week were the average. Eight of 300 samples were discarded. The cfu/100mL level stayed below 5, which is excellent.

The final filter actually acts as a barrier for particles that could enter the distribution loop. Even though 0.1 or 0.2 μm absolute filters are used, they do not perform a sterilizing function.^7,8 With a properly designed system, virtually no bacteria will reach the final filter.

A properly designed water system will control bacteria in ambient distribution loops by inoculation prevention and nutrient deprivation. Many ineffectual articles have been written about the velocity of the water, the material of construction, and the surface finish. None of these remove or control biofilm in the distribution piping. Gary C. Gray wrote a comprehensive review on recirculating velocities and materials of construction.⁹ Gray summarized, "There is not a single velocity upon which recirculating high purity water systems can be designed and operated to control biofilm formation."

REDUCING COSTS OF WFI SYSTEMS

WFI is expensive; two areas of possible cost reduction are capital costs and operating costs. Historically, most WFI systems have used the temperature of 80°C for storage and distribution. It is now generally accepted that 65°C is just as effective for microbiological control.

¹⁰

The lower temperature results in heating and cooling energy reduction.

The Three Phases of Validation

WFI contains dissolved metals, which might be of concern in some applications. The USP has eliminated the test for heavy metals, but the EMEA still has a specification of <0.1 ppm, which is often exceeded when measured by inductively coupled plasma mass spectrometry (ICP/MS). One way of reducing the metals content is to use polyvinylidene fluoride (PVDF) for some of the piping. George Fischer Company has produced a cost estimate, which claims that PVDF is 35% less expensive than 316L stainless steel.¹¹ The still, storage tank pumps and heat exchangers remain as stainless steel components. The savings on various components of costs (they are not equally weighted) are as follows:

• Components (mostly valves) — 34%

• Installation (welding, and pipe hanging) — 14%

• Start-up (cleaning, passivation, borescoping) — 53%

• Qualification (including installation qualification; IQ) — 50%

Even if we eliminate IQ (it is somewhat suspect and comprises only 3% of costs), the overall savings are approximately 35 to 38%. An additional advantage to using PVDF is reduced rouging, which is an ailment of stainless steel. This reduces the need for cleaning and passivation of the stainless steel components.

THE FACTORY ACCEPTANCE TEST

Clients are often amazed at the cost of commissioning and validating a compendial water system.

¹²

The procedures were established by the 1993 FDA guide, which does not have the force of law.

¹³

ISPE suggests that the guide's basic tenets be followed and applied with a value-engineering approach.

⁴

Let's start with the factory acceptance test (FAT). Most high-purity water systems are built as skid-mounted units at the vendor's site. It is not practical to run wet testing with resins and RO membranes. The following should be included in the FAT:

• Check P&ID by redlining any inaccuracies.

• Review cGMP compliance issues.

• Check for complete tagging and labeling.

• Check to see that operators and maintenance personnel have proper access to all the equipment.

• Check that the control system is functioning properly and all alarms are correctly activated.

• Check valve settings to agree with the valve checklist.

A log sheet is required for each of the above steps. The FAT can be considered as pre-validation, and the above documentation should be attached to the validation protocols and the summary report.

START-UP AND COMMISSIONING

The installed system requires commissioning before the actual validation can begin. The first step would be to confirm any changes, since the FAT are properly documented. Commissioning is defined by FDA as "The process of ensuring all building and process systems are designed, installed, functionally tested and capable of operation in conformance with design intent."

¹⁴

The start-up and commissioning are the responsibility of the vendor who built and installed the system. Representatives of the designer and owner should be present.

We always hear, "What is included in the commissioning and what is contained in the installation and operational qualification?" Many opinions have been expressed,¹⁴ but a good guideline would be to try to put as much as possible into commissioning. If an item has been covered in commissioning, it need not be repeated in later qualification steps. The validation master plan will spell out the documentation and its exact location in completed validation protocols.

VALIDATION

FDA's "Guide to Inspections of High Purity Water Systems" suggests validation procedures.

¹⁵

Remember, this is only a guide and does not have the force of law. We have included excerpts from the guide in a box.

The guide raises a number of questions. What is each step in the purification process? What do you test for after each step in the purification process? If you consider such units as multimedia filters, softeners, and carbon beds as purification steps, validation will be very costly and result in questionable data. However, if you break down the system into pre-treatment and post-treatment, using a risk assessment approach, the data will be more meaningful.

Validation of a high-purity water system is a long and expensive process. Since we have a well-designed system, the cost-effective approach would be to designate two weeks of intensive testing for each of the first two phases. After that, our understanding of weekly testing is that it should be based on the normal schedule of all users. If there is a weekend shutdown, the week is only five days. Hopefully, with the increase in the use of risk assessments, some of the time and costs may be reduced.¹¹

RUN COOL, RUN CHEAP

This article presents many concepts and ideas for designing, operating, and qualifying pharmaceutical and biopharmaceutical high purity water systems. We have deleted heat-sanitizing and strong chemicals everywhere except for WFI. The water system, properly designed, should require only one scheduled day of service per year. A well-designed high-purity water system will accelerate an efficient and cost-effective commissioning and qualification program.

ACKNOWLEDGEMENT

The authors thank William J. Penswick for supplying both analytical data and objective editorial comments.

REFERENCES

1. Baird A, Sommer K, Williams, R. Comparison of high purity water for microelectronic and biopharmaceutical facilities.

Pharmaceutical Engineering

2001 Sep/Oct; 21(5):34-46.

2. ISPE. Baseline pharmaceutical engineering guide. volume 4: water and steam guide. Tampa (FL): ISPE; 2000.

3. Bjurstrom EE, Coleman D. Water for Injection System Design. BioPharm International 1987; 1(10):42-47.

4. EMEA. Note for guidance on quality of water for pharmaceutical use. CPMP/QWP 158/01 Revision, EMEA/CVMP/115/01 Revision 2002 May. London. Available at www.emea.eu.int/pdfs/human/qwp/ 015801en.pdf

5. Govaert R, Livingston, RC, Fulcher J. Thermoplastic piping systems for bioadhesion control strategies in life science water systems. Ultrapure Water 2004; 21(3):39-42.

6. Dow Chemical Company. FilmTec ROSA. Version 5.4. [computer software]. Midland (MI): Dow Chemical Company; 2003.

7. Meltzer TH, Livingston RC, Jornitz, MW. Filters and experts in water system design. Ultrapure Water 2003; 20(8):26-29.

8. Meltzer TH, Jornitz MW, Tetzlaff RF. FDA on filters in water systems at points-of-use, storage and distribution. Ultrapure Water 2004; 21(1):40-42.

9. Gray GC. Recirculation in velocities in water for injection distribution systems. Pharmaceutical Engineering 1997 Nov/Dec; 17 (6):28-33.

10. Martinez JE. Hyperthermophilic microorganisms and USP hot water systems. Pharmaceutical Technology 2004; 28(2):50-62.

11. George Fischer. SYGEF HP piping systems; benefits for life sciences applications. Section 4.4. Tustin (CA): George Fischer; 1998.

12. Tashijan J. The problem of over regulation, over engineering and over validation. Pharmaceutical Engineering 2000 Jan/Feb; 20(1):8-14.

13. The discussion on commissioning and qualification is continued in the March/April 2001 issue of Pharmaceutical Engineering.

14. Signore AA. Good commissioning practices: strategic opportunities for pharmaceutical manufacturing. Pharmaceutical Engineering 1999 May/June; 19(3):56-68.

15. FDA, Office of Regulatory Affairs. Guide to inspections of high purity water systems. Available at: www.fda.gov/ora/inspect_ref/igs/high.html