The design of pharmaceutical water systems has always been part science and part alchemy, and unfortunately, it is not likely to change in the near future. Daily rhetoric is rife with statements from informed and intelligent people alleging design requirements that do not actually exist.

Take, for example, the use of bacteria-retentive filtration in a water system. For years, variants of the following alleged statement have circulated verbally: "FDA doesn't allow filters because it considers them to be band-aids on a badly designed system." As a result, many systems were designed without filters, rooted in a fear that the US Food and Drug Administration would disapprove. Meltzer et al., after researching this very subject, wrote that current FDA staffers indicated they would not disapprove a system simply because it contained these filters (1). Was this statement ever really made?

Written guidelines . . . or lack thereof

As far back as FDA's 1993 Guide to Inspections of High Purity Water Systems, one can find comments that, taken out of context, could be interpreted as support for either side of the argument.

For example, in that Guide, Section "X-Reverse Osmosis," paragraph 6 states, "The systems also contain 0.2 micron point of use filters which can mask the level of microbial contamination in the system" (2). It also goes on in the same paragraph to state, "If filters are used in a water system there should be a stated purpose for the filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed" (2).

Hence, in spite of the urban legend, it does not appear that FDA ever took a definitively negative stance against bacteria-retentive filtration, although some individual inspectors did so, possibly based on a specific system design or set of individualized circumstances.

What's missing.The normally accepted design criteria for US Pharmacopeia (USP) water systems (purified and water-for-injection) are neither published by FDA nor are they tabularized in a recognized volume for easy review and discussion, although much is written about them by industry pundits. Nonetheless, most or all of the writings include at least some of the items listed in the sidebar, "Commonly accepted design criteria for USP water systems." Some of the items listed in the sidebar are supported in reliable resources, but many are not, and few confirmations exist in regulatory print.

Regardless of whether these items are documented in the literature or not, they are very often accepted by owners, engineers, designers, users, validation experts, and operations personnel as rules or laws.

The good news is that none of these features, properly applied, have ever compromised a water system, although some absolutists have come very close. Consider the example of the engineer who insisted an 1100-ft long, 2-in. line be pitched ⅛ in./ft even though the roof elevation was only 12 ft (it took a contractor with a jackhammer to make the point).

Microbial control. What is paramount and possibly not obvious is that of the items listed in the sidebar, every one relates either directly or indirectly to microbial control or sanitization of the system.

The reason for so much focus on sanitization is that achieving the required chemical purity for USP waters (they're basically the same for purified and water-for-injection) is fairly simple with available technologies. Keeping the system under microbiologic control, however, takes finesse.