An important factor in any cleaning program is the design and configuration of the equipment being cleaned. However, the type of equipment, its accepted design, the residue acceptance criteria, and product quality expectations vary from one application and industry segment to another. Therefore, this section provides simply a technical basis and only general guidelines about key equipment-related issues to consider when designing a validatable cleaning process.
The preferred process design approach is to clean all surfaces in place without the need to disassemble and manually clean. This is possible only when the design of the process equipment allows the cleaning solution to make adequate contact with all surfaces that need to be cleaned. If the TACT cleaning parameters (time, action concentration, temperature) can be met across all surfaces and all the other factors we have discussed thus far have been considered, the desired cleaning effectiveness should be achieved. Unfortunately, many production systems are designed and integrated without enough thought for how they must be cleaned, which leads to excessive disassembly and manual cleaning, and consequently higher operating and cleaning validation costs. This section discusses production equipment design considerations, most of which relate to cleaning equipment efficiently in place. The key issues include cleaning process flow rates and coverage in pipes and vessels, equipment design issues associated with various process equipment and components, materials of construction, surface finish, and drainability of equipment and its effect on cleaning process effectiveness and efficiency (Voss, 1996).
Flow and coverage in process piping
Process pipes are typically cleaned in place by flowing cleaning solutions through the piping. Since piping is not easily subjected to visual inspection, having a consistent, validated process that uses proper design and operating practices is key to ensuring drug product safety. Inadequate cleaning of process pipes could be due to two general issues:
Flow through pipes
At very low flow rates, the flow characteristic in a pipe is laminar. Laminar flow in a pipe is characterized by a parabolic velocity profile as shown in figure 1 with little mixing in the radial direction. As the flow rate is increased, turbulence begins to set in when a non-dimensional parameter, the Reynolds number, reaches about 2000 for a straight stretch of pipe. The fluid turbulence becomes more significant as this number increases.
Fig. 1: Laminar vs. turbulent flow in pipes
The Reynolds number can be expressed in commonly used US dimensional terms by the equation:
Re = 3162 Q/dk
where Q is the flow rate in gallons per minute, d is the inner diameter of the pipe in inches and k is the ratio of the viscosity in centipoise to the specific gravity of the liquid flowing through the pipe. At a minimum, the flow rate in a pipe during the cleaning process should be large enough to result in turbulent flow. Achieving turbulent flow is important to provide adequate mixing of the liquid. As will be discussed in more detail, merely achieving turbulent flow in a pipe may be insufficient for providing full coverage in pipes with instruments or dead legs. A flow velocity of at least 5 ft/s (1.5 m/s) is a commonly accepted guideline for cleaning piping systems.
Fig. 2: Recommended flow velocity in pipes
The 5 ft/s velocity typically translates to a Reynolds number of greater than 30,000 or more, depending on the diameter of the pipe. Table 1 outlines typically recommended flow rates of various tube sizes. When large diameter pipes (greater than 3 inches) are involved, as in overhead risers in an API manufacturing facility, the flow rates required to achieve a 5 ft/s velocity could become excessive and impractical.
Table 1: Recommended flow rates to achieve 5 ft/s
In such situations, the 5 ft/s velocity criterion may at times be compromised. However, careful attention must be given to ensuring that cleaning solution coverage can be adequately achieved across all surfaces and any air or vapor trapped, particularly in downward flowing pipes, can be removed. If coverage cannot be achieved by fluid flow through the pipe, the pipe may need to be cleaned using spray devices by treating it like a process vessel.
The action or shear force acting on the surface helps dislodge the residue and is therefore an important parameter. This shear force does not necessarily directly correlate with the Reynolds number, but is higher as the flow velocity increases. The relationship between velocity and shear stress on surfaces can be found in text books dealing with fluid dynamics. The effect of velocity and pipe wall shear stresses has been discussed in literature, and its effect on the removal of bacterial spores in a CIP application has been reported (Biel et al., 2007).
When pipes include bends, valves, and tees, the cleaning effectiveness is altered. In a recent study (Prosek et al., 2005), it was shown that the amount of residue per surface area increased when a pipe included bends and it increased by a larger amount when a pipe included valves.
Coverage in dead legs
Dead legs are sections of tubing which lead to a discontinuity of flow, typically at a valve, sensor or sampling port. The number of dead legs should be minimized and if dead legs are unavoidable, the length to internal diameter ratio (as illustrated in figure 3) should be 1.5 or less. The diameter refers to the diameter of the dead leg and the length is measured from the inside wall of the main pipe to the end of the dead leg.
Fig. 3: Recommended L/D for dead legs
Minimizing the number and L/D on dead legs would imply seeking the shortest tees. Several manufacturers of fittings now offer compact tees, some of which are flush with the inside of the pipes.
The orientation of the dead legs should also be such as to allow for cleaning solution coverage and drainage. Figure 4 illustrates that a dead leg orientated in upward position can trap air or vapor resulting in poor contact of the wash solution and poor rinsing. A dead leg orientated in the downward position would allow full coverage of the cleaning solution and the rinse solution but poor draining. The downward orientation can allow particulates to settle as well as offer an opportunity for microbial blooms. A dead leg with an LID of 1.5, oriented horizontally with a slight pitch for the dead leg to allow for draining, has been shown to allow full coverage at a velocity of 5 ft/s.
Fig. 4: Orientation of dead legs