Europe catches up with membranes

Peter Jordain, technical manager, and Tanja Loehe, European pharmaceutical market manager, of Vivendi Water Systems outline the advantages of membrane processes over distillation

For many years both the American and Japanese Pharmacopoeia have allowed the use of different processes for the production of Water for Injection (WFI). The European Pharmacopoeia (EP), on the other hand, differs in that it prescribes the production process for WFI as distillation. These anomalies started a long debate in Europe, which resulted in a new water monograph for the EP in January 2002, incorporating a new specification: 'Highly Purified Water' (HPW).

The EP defines WFI (in bulk) as water for the preparation of medicines for parenteral administration. In general, the final rinse or cleaning of equipment and containers used in the manufacture of medicinal products must be conducted with the same grade of water that is used in the final stage of manufacture. As rinsing and cleaning requires large volumes of water, a considerable amount of WFI is used for these purposes and not directly in the medical product itself.

certain conditions

Considerable savings could therefore be made and product quality unaffected if the specification for WFI were maintained and the production method deregulated. Hence the reason for HPW.

HPW has the same quality specifications as WFI (see Table 1), but it differs from WFI in that it can be produced by a membrane process as an alternative to distillation. The use of HPW as well as Purified Water (PW) and WFI is described in a Guideline by the European Agency for the Evaluation of Medicinal Products (EMEA) published in May 2002; however, the use of HPW in pharmaceutical products is never directly prescribed.

The use of HPW for cleaning and rinsing equipment, containers and closures is handled in a separate part of the EMEA Guideline. In general, equipment for the production of sterile, non-parenteral products should be rinsed and cleaned with purified water or a higher grade if this is used in the manufacture of the product. For cleaning and rinsing of equipment for sterile, parenteral products, the Guideline defines WFI as the minimum acceptable quality but also states in a footnote that 'Where a subsequent depyrogenisation step is employed the use of Highly Purified Water may be acceptable subject to suitable justification and validation data'. This footnote allows manufacturers to replace WFI for final rinse under certain conditions with the more economical HPW.

reliable distillation

Due to its considerable energy consumption, distillation is an expensive process when compared with membrane processes (Table 2). Membrane processes remove micro-organisms and endotoxins physically from the water being treated and with proper operation are easily as reliable as distillation. This is true when considering that stills are not infallible and endotoxins can pass through them in entrained droplets.

Advances such as hot water sanitisation have made membrane processes eminently suitable for pharmaceutical applications, since hot water sanitisation offers several advantages compared with chemical disinfection. Chemical disinfection is effective only when the sanitising agent makes direct contact with the micro-organism and is therefore less effective at sanitising cracks and crevices. Heat, however, sanitises hard to reach areas, penetrates protective biofilm layers, and destroys bacteria completely in the process.

The conventional system for generating Purified Water consists of softening, reverse osmosis (RO) and continuous electrodeionization (CDI). Softening conditions the water prior to the RO and prevents scaling in the downstream processes. The RO unit removes most of the inorganic substances, TOC and bacteria from the softened water and provides the optimal feed for the CDI process.

A CDI module consists of alternating cation and anion permeable membranes with an anode on one side and a cathode on the other. The space between the membranes is filled with ion exchange resin. As RO product water (permeate) flows through the module, a DC electrical field continuously transports the anions and cations towards the anode and cathode respectively. The anions pass through the anion permeable membrane but further transport is prevented by the following cation permeable membrane, which repels anions. The reverse is true for cations. This creates alternating diluting (purifying) and concentrating (contaminant removing) compartments between the membranes.

meeting specification

Since the CDI also removes weakly ionised species like carbon dioxide, the final conductivity of about 0.2µS/cm consistently offers a large safety margin to the conductivity specifications.

A conventional system of this type may meet the microbial specifications for HPW but would require very frequent sanitisation to periodically arrest the regrowth of bacteria and thereby consistently to meet the specifications. Chemical disinfection is usually conducted manually and requires a long rinse cycle.

  Furthermore, since it is not possible to prove complete penetration of the chemical disinfection agent throughout all parts of the system, the first warning of an unsatisfactory sanitisation would be some time after the event - and probably too late - via the microbial monitoring programme. The efficacy of hot water sanitisation on the other hand can easily be verified by measuring the temperature of the system during sanitisation.

To meet the HPW specifications, a pre-engineered, skid-mounted system was designed that adds an additional membrane barrier as well as a fully automated hot water sanitisation programme to the conventional purified water treatment train (see Figure 1).

successful design

Ultrafiltration (UF) is used as the final membrane barrier against bacteria and endotoxins present in the product water from the CDI unit. Over the years, both RO and UF membranes have been used to remove endotoxins to produce pharmaceutical grade water.

Although the pore size of RO membranes is up to 100 times smaller than the pore size for UF, studies have shown that UF membranes are considerably more effective at removing endotoxins because of the superior hygienic design of the housings or modules into which they are assembled.

Endotoxin removal with UF proved so successful, that the Japanese Pharmacopoeia has allowed the use of ultrafiltration for the production of WFI since 1988. In addition, the research results from Japan and subsequent operational experience in Europe have resulted in Ultrafiltration being the technology of choice for non WFI, pyrogen-free water in Europe for the past two decades.

Although the first systems on the market were either steam sterilisable or hot water sanitisable, results showed that the hot water sanitisable systems were just as reliable as steam sterilisable but cost less and were easier to automate. As a result, hot water santisable systems are the preferred technology.

several advantages

Hot water sanitisation has several advantages: The temperature within the system is easy to control, monitor, continuously record and validate using in-line temperature sensors.

Furthermore, thermal mapping of the piping can prove that temperature has been achieved at all points of the system. Hot water sanitisation can be conducted automatically every week and since it requires very little rinse water can be brought back on line much quicker than the conventional system.

The water grade 'Highly Purified Water' means WFI quality without limiting the production process to distillation. Membrane systems that are properly operated and sanitised offer considerable cost savings in comparison with distillation.

The combination of proven RO/CDI and ultrafiltration technology as a pre-engineered and hot water sanitisable system enables a reliable, efficient and economical means of generating water with WFI quality, which by saving energy is also environmentally friendly.