In the healthcare industry, many patients are served by pharmacies that prepare drug compounds and dosages in local facilities. Unlike most of the drugs taken daily, drugs that must be administered intravenously for certain patients (cancer treatment patients, autoimmune disease patients) within hospital and infusion settings are often prepared in specialty pharmacies.
The United States Pharmacopeia (USP), in its USP Pharmaceutical Compounding Sterile Preparations and USP Hazardous Drugs-Handling in Health Care Settings documents, provides quality standards and practices to promote patient and worker safety, as well as environmental protection. Some of these practices address topics such as dispensing dosages, safe work practices, personnel training, exposure and other critical concerns. One of those concerns is facility and engineering controls.
Engineering controls can be imagined as concentric circles of protection surrounding the direct compounding area (DCA). The concentric levels of protection are commonly designated primary, secondary and tertiary. Primary controls are the most critical in that the DCA is entirely enveloped in filtered air, which is nominally ISO 14644-1:2015 Class 5 but much cleaner. Secondary controls consist of the HEPA-filtered cleanroom space wherein the primary engineering controls reside.
One of the most important secondary-control barriers to contamination in HEPA-filtered cleanrooms is room pressurization. Room pressurization levels between adjacent cleanrooms and surrounding uncontrolled spaces determine the direction of surplus airflow between those spaces. Rooms are commonly referred to as positive or negative pressure. Any room is positive relative to some other space and likewise negative to some other space. Any space pressure must be compared to some other space pressure to determine whether it is referred to as positive or negative.
In cleanrooms, we are often concerned with pressure differentials as low as 0.01 inches of water (inH2O), or 2.5 pascals (Pa). In the IP system of measurement, a common unit of thickness is a mil. One mil is equal to 1/1,000 of an inch, or 0.001 inches. Therefore, the pressure magnitudes that concern us in cleanrooms are ten mils, or even as low as one mil. A pressure difference of 0.01 inH2O is the equivalent of the pressure which would be impressed upon the bottom of a container having a column of water 10 mils—about as high as the thickness of your shower curtain. They are extremely small pressures indeed.
When cleanroom practitioners talk about ambient space and ambient pressure, the term ambient is arbitrary. The ambient space is typically chosen as the uncontrolled building space just outside of the controlled cleanroom space and is considered the arbitrary zero pressure from which to characterize the rooms’ pressures. This is a sensible choice since this space is presumably contaminant-laden and consequently serves a practical purpose for contamination-controlled spaces. The units of inches of water are used for this example (0.01 inH2O = 2.5 Pa):
The first fundamental law of understanding room pressures is that each room has its own unique pressure relative to ambient. This is the value which should be reported for the cleanroom pressure. Many rooms have more than one door and, consequently, more than one available pressure measurement pathway out to the ambient space. In Figure 1, the pressure in room D can be measured along two different pathways—Pathway 1: Ambient less ∆P room “A” less ∆P room “B” less ∆P room “C” less ∆P room “D,” or Pathway 2: Ambient less ∆P room “D.” The final pressure in room D relative to ambient must be the same ceteris paribus, regardless of the pathway taken.
Reading in the fashion of Pathway 1 is called a cascade. The second fundamental law of understanding room pressures is that room pressures add algebraically. The correct way to report cleanroom pressure differentials is room A – room B = (value), meaning that the value is the algebraic difference of the pressure in room A minus the pressure in room B. This is known by having the positive gauge terminal connection exposed to room A and the negative gauge terminal connection exposed to room B. If this notation is used, then the following relationship applies: room B – room A = (- value)
In Figure 1, the blue arrows represent the differences in room pressures, and consequently, are typically located across the room’s doors, indicating the physical location of the measurement. The pressure differences should always be stated as positive numbers. This might be somewhat confusing at first, but consider that there are only two possibilities, i.e.: there is no difference, or there is some difference.
The concept of a negative difference is nonsensical in this context. The arrows represent the direction of airflow with the understanding that air, like any fluid, always flows from a region of higher pressure to a region of lower pressure. The bordered values in the center of each room represent the unique room pressure algebraic sums relative to the arbitrarily chosen ambient.
Cleanroom pressure specifications can be presented in one of two fashions: door-to-door or cleanroom with respect to ambient. The number of doors in a cleanroom complex must equal or exceed the number of rooms. More likely than not, there are more doors than rooms. This situation can lead to irreconcilabilities in the room pressure schedule. Figure 2 illustrates this inconsistency.
Counting the ambient space as one of the rooms, the six rooms are connected by nine doors. The arrows represent the client-specified differential pressure relationships across the various doors, with each arrow representing a specified value of 0.02 inH2O. The rectangles inside of the rooms represent each room’s unique pressure relative to ambient, just as in Figure 1. The problem is identifying the solution set of the six-room pressures that satisfies all nine door arrows.
If we look at the door between room E and room B, room E is specified to be 0.02 inches positive with respect to room B. However, room B is specified to be 0.04 inches with respect to ambient for the two arrows in room A to be satisfied. Room E must be -0.02 inches with respect to ambient for the arrow between ambient and room E to be satisfied.
But this situation immediately leads to an inconsistency. Namely, if room E is -0.02 inches with respect to ambient and room B is +0.04 inches with respect to ambient, then the arrow between room E and room B must point from room B into room E, not vice versa. Furthermore, the magnitude of the differential pressure between room E and room B must be 0.06 inches, not the client-specified +0.02 inches. The lesson is that unique room pressures determine door differentials; door differentials do not determine room pressures.
A current misapplication of this critical principle is found in the United States Pharmacopeia (USP) <797> and USP <800> regulations. Taken collectively, the requirements are: (1) the positive pressure rooms such as non-HD compounding relative to ante room and/or the ante room relative to ambient must be +0.020 inches ≤ P ≤ +0.050 inches, and (2) the HD compounding pressure must be -0.010 inches ≤ P ≤ -0.030 inches to all adjacent spaces. Both regulations are door-door pressure specifications.
Now, let’s look at two common compounding architectural floor plans. The first is the nested HD compounding layout where the HD compound is inside of the non-HD IV compounding room, as shown in Figure 3. This is an obsolete architectural plan layout for new facilities, but one which is found in legacy compounding pharmacies.
In the second type of facility layout, the common ante room layout, the HD and IV compounding rooms are accessible through the same ante room, as shown in Figure 4. There are many other variations in compounding room layout but for now we will address just these two. In both layouts, there are three controlled spaces: ante room, non-HD (IV) compounding and HD compounding.
Figure 5 tabulates a range of possibilities for the three rooms’ pressures relative to ambient. In this table, the assumption is that the IV compound is +0.02 inches relative to the ante room, in accordance with USP regulations, which in turn, is varying from 0.020 to 0.050 inches relative to ambient per USP regulations. In the figure, the HD (CHEMO) compounding room varies from -0.030 to +0.030 inches relative to ambient under each of the four pressure permutations for the ante room. The center and right-hand thirds of the table detail the resultant door-door differential pressures. Green indicates that the room-room differential pressure is within specification, while red indicates that the room-room differential pressure is outside of specifications.
The results are apparent. There is only one possible permutation (for each allowable IV compounding – ante room acceptance value 0.02,0.03,0.04 and 0.05 inches) of room pressures relative to ambient that will satisfy the USP door-door regulations, which can be seen in trial 3. The USP regulations can never be satisfied in the nested HD design and there is only one possibility, as stated, for the regulations to be satisfied in the common ante room design.
We encounter another insurmountable problem, however, with the apparent equilibrium in trial 3. For the door-door USP regulations to be satisfied as in trial 3, the HD compound must be simultaneously maintained such that the combined errors of both HD and ante do not exceed the 0.004 inH2O requirement. The most sophisticated commercially available room pressure control systems can only maintain tolerances of hundredths of an inch water column, not thousandths.
By ignoring the fundamental principle that unique room pressures determine door differentials and door differentials do not determine unique room pressures, the USP is mandating an impossibility.
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