A New Qualification Approach for Mobile Purified Water Systems
The unavailability of a backup pharmaceutical water system has been a severe limitation for pharmaceutical manufacturers. Until recently, qualification concepts that adhered to current Good Manufacturing Practice (GMP) guidelines hindered the rapid setup of a water system. A new, tailor-made qualification concept for mobile water treatment has been developed to align with guidance from various health authorities and organizations. It is now possible to set up a temporary purified water source for pharmaceutical applications in less than 3 weeks.
Mobile water treatment is a widely used solution in power, chemical, and numerous other process industries. Depending on the product water specification, different water treatment technologies are installed on a rack or in a container. The water treatment unit is then transported by truck and set up at the point of use. After installing the media supplies and connecting the necessary interfaces, experienced technicians can perform a quick startup. The water treatment system is then ready to use, can be rented for several days or weeks, and is easy to remove. However, these solutions are not intended for GMP-relevant applications.
GMP regulations require an in-depth equipment qualification, which includes performance qualification (PQ), before the water can be used for pharmaceutical purposes. During PQ, the unit must perform over several weeks. In addition to all other onsite qualification activities that must be completed before starting PQ, the traditional qualification process may require up to 4 months. This is why mobile water solutions are not commonly used in the pharmaceutical industry.
A market for mobile water systems in the GMP sector exists: many people ask local water treatment manufacturers for mobile solutions. Possible industry needs include:
- A backup solution is needed during maintenance or repair of an existing system.
- A new water treatment unit must be placed where the old one is installed.
- An existing water treatment unit must be replaced without shutting down manufacturing.
- An existing purified water system has microbial issues and remediating the issues takes considerable time.
- Washing areas must be relocated temporarily and no purified water outlet is available.
Purified water systems must always be easily and regularly available in the facility. If a tablet press has a defect, another qualified one can be used and few, if any, other processes at a site are impacted by the breakdown. A water system, by contrast, supplies all pharmaceutical facility applications: dispensing, processing, filling, equipment and machine cleaning, and potentially even air humidification. A water system issue would even shut down packaging lines because their format sets could not be cleaned. In other words, a water system breakdown stops all facility operations.
How much does production interruption cost? This question cannot be answered easily, as many factors must be considered. Could downtime be used for other activities, such as maintenance? Another important factor is that if a company cannot ensure patients’ medicine supply, the patent for that medicine may be temporarily negated1.
These factors result in the need for a highly reliable water system in a pharmaceutical facility. This was also why the author considered solutions that increase the availability of water. Until now, it was not possible to quickly set up and qualify a pharmaceutical water system. This situation provided the motivation to develop a new qualification concept and discuss it with different health authorities and organizations:
- Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten (Germany’s central authority for health protection with regard to medicinal products and medical devices)
- US Food and Drug Administration (FDA)
- US Pharmacopeia (USP) Chemical Analysis Expert Committee
- German-Austrian-Swiss ISPE Community of Practice “Water and Steam” (ISPE CoP D/A/CH)
Each organization offered valuable input that was used to refine the qualification strategy. Some of these ideas are discussed in the Qualification Risks section. Finally, a qualification concept could be created that was recognized by all parties and accepted for use, but it must be approved by pharmaceutical manufacturers. With this concept, the period from installation to release of the water for pharmaceutical use can be reduced to less than 3 weeks. In contrast, the traditional qualification approach before release of the water normally takes up to 4 months.
Through the existing mutual recognition agreements2, a wide range of countries is covered by the involved parties. In addition, as many experts admitted, there is no existing law or guidance that prohibits the use of mobile water systems; the challenge is to provide a quick but sufficient qualification.
A typical mobile water treatment system may be installed inside a standard 20- or 40-foot container for truck transport or it can be placed on a rack with rollers. This type of unit is transportable and has defined interfaces for feed water, wastewater, power, product water, and further media as required. The subject of this article is mainly the purified water generation unit. Storage and distribution systems must be installed inside the manufacturing building, and the water purification unit is connected to an existing tank. Possible solutions are shown in the photos on.
The new qualification concept addresses numerous risks that only occur in mobile systems.
- Purified water is considered a medicine excipient. Consequently, the water must be released for manufacturing purposes by the head of quality control (QC). How does QC obtain the relevant data needed for the release of the raw material?
- Which feed water quality should system design be based on? Feed water quality is unknown when the unit is designed.
- While the mobile water unit is under construction, the equipment supplier does not yet have a customer to provide requirements. A user requirement specification (URS) for the equipment should be made prior to fabrication by the equipment supplier. This document can be provided to the user for approval or to be used in the development of the user’s own URS.
- It is assumed that the unit will not be connected to the local TCP/IP network and must be secured according to data integrity guidelines. How can the data be stored and transferred in a secure manner? The data must also be deleted from the water system when it is subsequently uninstalled.
- What happens while the unit is in transport? Resins or filter gravel layers may become mixed if the unit vibrates. In addition, a softener cannot be entirely dried again after wetting. This must be considered because any remaining water in the softener might pose a risk to microbial proliferation in the vessels.
- The risk of microbial contamination is increased when the system is transported. Cleaning and disinfection tasks should be done.
- Maintenance tasks may be increased if the unit needs to be transported. In addition, ownership for all typical maintenance tasks must be established for the mobile unit.
- During transport, single parts or components might be damaged. Checks after transport and a decommissioning procedure are recommended.
Mobile water systems are feasible for different GMP applications and can help avoid purified water shortages at the pharmaceutical site.
Most notably, the lack of specific requirements at the beginning of the project is of particular concern. The only possible solution seems to be selecting a custom water specification. However, drinking water regulations worldwide cover at least 50 compliance parameters. Which ones apply in a certain instance, and which specification range should be set in advance? The presented qualification concept provides a recommendation for a suitable feed water specification. A typical flow scheme for a mobile water treatment system is shown in Figure 1.
The typical qualification procedure for any GMP machinery consists of design qualification (DQ), installation qualification (IQ), operational qualification (OQ), and PQ. To set up mobile water systems, two main aspects had to deviate from the common approach:
- An IQ/OQ process of a water system at the pharmaceutical site normally takes several weeks. Commissioning is performed in this period as well. To quickly have a portable purified water supply ready, this period had to be shortened.
- Normally, under international PQ requirements, a water system will be in a test phase (Phases I and II) for 4 to 8 weeks before water can be released for pharmaceutical purposes. Furthermore, Phase III testing is conducted after release to take into account seasonal variations of feed water and verify the operation over a year. To ready a portable water system, this PQ step had to be modified.
- 1. Federal Ministry of Justice and Consumer Protection. “Medicinal Products Act. Section 79: Authority to Permit Exceptions in Times of Crisis.” April 2016. http://www.gesetze-im-internet.de/englisch_amg/englisch_amg.html#p1788
- 2. European Commission. Industry, Entrepreneurship and SMEs. Single Market and Standards. “Mutual Recognition Agreements.” Accessed 11 February 2018. https://ec.europa.eu/growth/single-market/goods/international-aspects/mutual-recognition-agreements
To support these needs, the mobile system qualification strategy comprises two main elements: the qualification and the “prequalification,” as shown in Figure 2. The first one is carried out at the supplier’s site. Tests to verify adherence to ASTM E25003 principles may be performed during commissioning activities. To fulfill “Good Documentation Practice,” it is necessary to review and approve those test results as part of the qualification in the commissioning protocol/report.
The ASTM E2500 qualification approach strongly relies on subject matter expert knowledge and engineering documentation for any type of testing. This practical strategy is part of the mobile water system qualification plan.
The unit prequalification, including PQ, at the supplier’s site justifies rapid qualification at the installation site. To compensate for the missing user experience at the site, several additional actions such as monitoring or training activities must be done. In total, a suitable process control strategy has been developed and is part of the tailor-made qualification concept (see Figure 2).
As Figure 2 illustrates, the entire unit qualification process is divided in two parts: one at the supplier’s site, which is called prequalification, and one at the pharmaceutical site. After completing the prequalification phase, the unit is ready to be rented to the pharmaceutical customer.
In the next step, the mobile water system is transported to its destination next to or within the GMP site, where it is connected to the existing storage and distribution system. To complete this, a change request must be set up by the customer according to the site’s pharmaceutical quality system. In case of outside placement, weather conditions must be assessed. Usually from the moment the system arrives at the site, all tasks must be performed rapidly, which is common in rental use. The author estimates 3–5 working days to locate the unit, connect all (prepared) interfaces, and perform the necessary IQ/OQ testing that could not be performed before delivery or that may have to be repeated onsite. After successful completion and approval of the OQ report, the water treatment unit must demonstrate robust operation in the scope of the PQ. Figure 3 shows how the timeline has been modified for the new approach.
Ensuring water safety is a critical aspect of using mobile water treatment systems. During the concept review, agency regulators specifically recognized that this accelerated approach to qualification involves more risks. In addition, neither the supplier nor the pharmaceutical manufacturer will have any significant experience with this water system combined with specific local feed water. The additional risks due to rapid startup procedure and lack of experience must be offset elsewhere. Especially in the first weeks, a high degree of control is needed until sufficient experience has been gained. After releasing the water for pharmaceutical purposes, PQ continues until 1 year of data has been acquired or until the unit is decommissioned.
Pharmaceutical manufacturing site technicians will also lack experience with the mobile water system. Although they will be trained how to operate the unit, the process of establishing standard operating procedures may take more time than is available at the site. Consequently, several tasks must be clearly described in the operator’s manual or be automatically performed by the control system. In total, the new qualification strategy describes a suitable contamination control strategy for operation of a mobile water treatment system. Additionally, the new Annex 1 draft to the GMP guidelines4 requires establishing a contamination control strategy for aseptic manufacturing. According to the new annex, affected companies will also have to develop a strategy for their stationary water for injection (WFI) or highly purified water (HPW) system (if still in use).
Mobile Water System Designs
Mobile water treatment solutions can be designed in different ways to fit different needs and applications. They can be installed on rolling racks, in intermodal ISO containers, on trailers, or as decentralized small systems for the supply of single outlets (e.g., in a temporary washing area). Which process technology is used depends on the desired range of applications and how the unit is transported. The qualification concept is applicable for all design types. Examples of these designs are shown in the photos on pages 64 and 66. Additional technologies may be used to ensure safe operation and to compensate for additional risks associated with temporary use.
- 3. American Society for Testing and Materials. “ASTM E2500-13: Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biophar-maceutical Manufacturing Systems and Equipment.” West Conshohocken, PA: ASTM International, 2013. https://www.astm.org/Standards/E2500.htm
- 4. European Commission. Health and Consumers Directorate-General. EudraLex, Volume 4, Annex 1. “Manufacture of Sterile Medicinal Products.” 20 De-cember, 2017. https://ec.europa.eu/health/sites/health/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf
The required amount of water and pharmaceutical site conditions must be considered before renting a water system. The following sections discuss a total cost calculation for a water treatment system supplier and a pharmaceutical manufacturer to provide basic economic information for both parties.
Mobile Water System Supplier Example
The following calculation is based on a capacity of 1 cubic meter of purified water per hour (1 m³/h) according to relevant worldwide pharmaceutical monographs. Estimated costs are based on experiences from European countries. Because all media are supplied (and paid for) by the pharmaceutical company, they are only included in the Pharmaceutical Manufacturer Cost Calculation, not here.
It is assumed that a pharmaceutical water treatment system including testing, setup, prequalification, documentation, and the additional requirements to make the system mobile would cost €250,000. (At the time of writing, €1 is approximately equal to $1.12 USD.) The typical rental cost for the water system is calculated as €7,000/week, with transport and fast-track qualification at the customer’s site being charged separately (see the Pharmaceutical Manufacturer Cost Calculation). This would result in an amortization of the unit for the supplier after approximately 41 weeks of rental, including €10,000 of maintenance cost per year.
A typical rental period is assumed to be 10 weeks, including 2 weeks of PQ. If two customers rent the unit every year (20 weeks of rental per year in total), it would take approximately 2 years to cover the cost of the water treatment unit. Assuming a typical system lifetime of 10 years, the supplier would have approximately 8 years to earn profit with the mobile unit after amortization. Maintenance and repair costs of €10,000 per year can be assumed.
This calculation demonstrates that the supplier can earn a significant profit. As shown in Figure 4, the total return on investment for a mobile unit over its entire lifetime can reach more than €1 million.
|Transport, commissioning, and qualification costs||€20,000|
Pharmaceutical Manufacturer Example
Estimating all expenditures for the pharmaceutical manufacturer is more difficult and complex than for the supplier company. As discussed previously, the possible loss caused by unplanned downtimes can only be estimated as an opportunity cost, but the reputational damage and potential loss of business would be extremely high if the company’s products go out of stock. Furthermore, a water system breakdown stops all GMP manufacturing activities across the entire site.
Calculations are based on data from the Water Treatment System Supplier example for easy comparison of both business cases. A daily consumption of 8 m³ shall be met in the facility, for which the capacity of 1 m³/h described previously may be suitable. The facility operates 6 days a week, so the weekly amount of water is 48 m³. As mentioned, the treatment plant rent is €7,000/week, which leads to rental costs of €70,000 for a 10-week lease.
The cost for transporting, installation, extra piping, commissioning, and fast-track qualification is calculated as €20,000 for a single event per customer.
The total water system operating costs have rarely been calculated in the past because many of the costs, including the following, are difficult to estimate:
- Root cause investigations
- Feed water and waste water costs
- Compressed air
- Cooling energy
- Consumables, chemicals
- Spare parts
- Trending/product quality review activities
- Operational costs (trainings, daily inspection activities, etc.)
The author published a total life-cycle cost calculation5 that is used for further consideration (Table 1). An average cost of €14 per cubic meter of produced purified water has been calculated to cover all mentioned expenses. Over the total term of the lease (10 weeks), 480 m³ purified water will be used, for a total cost of €6,720, and the total cost for the 10 weeks would be €96,720.
The only possible solution seems to be selecting a custom water specification. However, drinking water regulations worldwide cover at least 50 compliance parameters.
As an alternative to a mobile water treatment system, water may be bought in intermediate bulk container (IBC) totes (usually approximately 1 m³ volume) and filled manually into the existing storage tank. However, there are several risks to consider:
- Compared with a mobile water treatment system, use of water in containers requires regular sampling of a greater number of parameters (according to USP 1231).
- Raw materials in bulk must be sampled according EU GMP Annex 8 (statistically valid methods), which leads to very high monitoring costs.
- At least 60 m³ water would have to be transported to and through the facility every week.
- Purified water in containers is not always suitable for the preparation of solutions.
Assuming a price of €250 per cubic meter of water in an IBC container, €2,000/week transport costs, and €1,000/week sampling and testing costs, the total water supply price would be €15,000/week, or €150,000 over the entire period.
Clearly, a mobile water treatment unit is not only easier to handle but also the cheapest option for the pharmaceutical manufacturer to establish backup capacity in the facility.
- 5. Röder, F. Chapter 6.A. In Pharmawassersysteme Wirtschaftlich Betreiben (Pharmaceutical Water—Ingredients, Limits and System Concepts: Ultrapure Water for Manufacturing and Laboratory [GMP Expertise]). Schopfheim, Germany: Fritz, Maas & Peither Publishing, 2017.
The new qualification strategy for mobile water systems has been discussed with experts and authorities from all around the world. Using it, the qualification procedure can be shortened to a duration of less than 3 weeks from installation to release of the water for pharmaceutical purposes. Mobile water systems are feasible for different GMP applications and can help avoid purified water shortages at the pharmaceutical site. In many cases, local quality assurance policies prohibit the use of a mobile system because the qualification time frame is abbreviated or simply because of a lack of experience. However, the concept offers advantages for the health authorities. Their mandate is to provide sufficient amounts of high-quality medicine for the public, and a mobile water system helps ensure the timely supply of medicine to the market.6
- 6. European Commission. Health and Consumers Directorate-General. EudraLex, Volume 4, Annex 15. “Qualification and Validation.” 20 March, 2015. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2015-10_annex15.pdf