Strong cleaning action on all product-contact surfaces  not only minimizes the risks of contamination and of system malfunction, but  also enables cost-efficient cleaning. Dead legs, pockets and crevices, air  pockets, and equipment surfaces are common design pitfalls, often seen in the  pharmaceutical industry, that impair equipment cleanability.

It is widely understood that dead legs should be avoided  or minimized in a system (see Figure 1). Some guidances state that the L/D (i.e.,  length/diameter) measurement for dead legs should not be more than 2—and, in  some cases, not more than 3 (see Figure 1). However, the relation between the  main-pipe velocity and the L/D measurement is often overlooked. High main-pipe  velocity makes the turbulence go deeper into the dead leg, and if the  turbulence or action is strong enough, it will remove the residues at the  bottom of the dead leg.

 
 Figure 1: Dead leg. (All figures are courtesy of the author).
 
 
 

 
 Figure 2: Velocity and L/D  measurement. 

In a 1997 article, Haga et al. presented  results from tests with various velocities in the main pipe in various L/D  measurements (1). They found  that for an L/D of 6, it is possible to clean the residue adequately if the  main-pipe velocity is higher than 1.5 m/s. They also found that for an L/D of  3, it is impossible to remove the residue if the main-pipe velocity is lower  than 0.7 m/s (see Figure 2).

No rule of thumb governs the depth of pockets and  crevices. Figure 3 shows a typical crevice found in pharmaceutical systems.  Many guidances state that crevices should be avoided or eliminated when  possible, a statement that seems weak considering that a crevice could be likened  to a dead leg with an L/D measurement of an astonishing 50–100, compared with  the normal 2–3. Following Haga et al., it would be impossible to achieve the  velocity required to clean the bottom of a crevice. Thus, pockets and crevices  should not exist in pharmaceutical systems, because they will always pose a major contamination risk.

 
 Figure 3: In many pharmaceutical systems, a hard-to-clean pocket is created between two metal parts and an O-ring  seal. 

Air pockets may be described as upside-down dead legs or crevices (see Figure 4). Although residues do not collect in an air pocket,  they stick to its surface. It is difficult to evacuate the air from these  pockets during the cleaning process, which means that the cleaning liquid will  not reach the top of the air pocket and, accordingly, will not clean it. Air  pockets therefore must be eliminated, or they will introduce a high risk of  contamination.

Surface finish is often considered a measurement of  hygienic design. The maxim is that the smoother the surface, the more hygienic  and easy to clean it is. But this principle is, in fact, open to debate. A 2003  study by Hilbert et al. tested the adherence of bacteria to several surfaces and  the cleanability of these surfaces (2). The surfaces, from 0.1 µm electro-polished to 0.8 µm mechanically polished, showed no  differences in adherence or cleanability. The main reason was the relatively  large size of the individual bacteria compared with the small size of the  surface imperfections. As long as the surface finish is below a roughness  average (Ra) of 0.8–1.0 µm, the bacteria are too  large to get trapped between the surface imperfections. 

However, in another study, Riedewald showed that when  bacteria accumulate in a biofilm, adherence and cleanability depend on the  surface finish (3). It is harder for biofilms to attach to a smooth surface, and  it thus is easier to detach them from such a surface.

The same is true for other sticky residues. A study at  the Institute of Technology in Kolding, Denmark, tested the cleanability of  surfaces spiked with a yogurt solution that had been oven-dried (4). This study  clearly showed that a surface with a low Ra value was easier to clean than one  with a high Ra value. The tested surfaces ranged from Ra of 0.15–2.4 µm. Electropolished surfaces also were easier to clean  than mechanically polished surfaces, which in turn were easier to clean than  pickled surfaces. 

Equipment designed correctly will avoid the above  pitfalls, thus facilitating safe and cost-efficient cleaning. The more cleaning  action that is applied on all product-contact surfaces, the easier and quicker system  cleaning will be.

Microbial Adhesion and  Biofilm Formation in the Food Processing Industry

 (Technical University of Denmark, Kolding, Denmark, 2007). 

Per-Åke  Ohlsson is global manager for Alfa Laval’s Pharma and Personal Care Market Unit 

Box 74, Rudeboksvägen 1, SE-221 00 Lund, Sweden, tel. +46 46 36 74 18, 

Articles

In the Mixer

Understanding equipment design and product-contact surfaces enables strong cleaning action.

Common Equipment-Design Pitfalls That Impair Cleaning

ACS Valves
 Rotary airlock valves for regulatory compliance


 ACS Valves’s Quick-Clean series of rotary airlock valves is designed to aid users in achieving compliance with regulatory standards. The valves feature the ACS RotorRail design that enables full validation access to the rotor and all internal surfaces of the housing without requiring disassembly of the endplate. The stainless-steel housings are machined to precise tolerances. Internal surfaces are polished to a No. 4 finish, and the ACS Valves’s clean-in-place-ready design eliminates internal crevices and joints, where contaminants can accumulate.

The valves’ inlet–outlet seal is produced with an eight-vane rotor design, which eliminates excess pressure loss through the system, ensures cost-efficient upstream- and downstream-material management, and reduces process energy consumption. The valves are available in 304 or 316 stainless steel, and in sizes from 6 to 16 in. with pressure differentials as high as 15 psig and temperature tolerance as high as 500 °F.

Terra Universal
 Compounding cleanrooms comply with 


Terra Universal’s compounding cleanrooms are suitable for compounding sterile injectables and other preparations in accordance with 

 <797> standards. An ISO 5 (Class 100) primary processing area with three high-efficiency particulate air filter–fan units provides a total of 1950 cfm (3315 m

/h) of 99.99% particle-free air (measured at 0.3 µm diameter).

The cleanrooms’ fan–filter units exceed 

 <797> particle-count and air-change requirements between the buffer room and the antechamber room. Users have a choice of polycarbonate and static-dissipative polyvinyl chloride panels. A powder-coated steel support frame creates a rigid, durable structure that requires no external bracing or ceiling support. The unit’s sliding vinyl curtain creates a separate antechamber that offers another level of protection to the buffer room from the ambient environment. The antechamber is also under positive pressure, and personnel can don garb or prepare materials, thus leaving the buffer room strictly for needed equipment.

PharmTech's monthly newsletter, Equipment and Processing Report, reviews the Editor's Picks for the January 2012 edition from ACS Valves and Terra Universal.

January 2012 Editor's Picks: Products from ACS Valves and Terra Universal

Innovation plays an important role in the pharmaceutical industry, including in manufacturing. Robotics is one area that offers opportunity for further advancement in areas such as fill–finish production.

In terms of accuracy and speed, robots far exceed what the pharmaceutical industry requires. But, for a long time, robots did not meet the industry’s requirements for aseptic manufacturing. Operators could not decontaminate robots with hydrogen peroxide in a way that could be validated. In addition, robots shed particles at unacceptable levels and often were made of materials, such as aluminum, that were not suitable for filling operations. But these problems have since been overcome, and technological advances are no longer necessary for drugmakers to implement robots. “They can do it today,” says Chris Procyshyn, CEO of VanRx Pharmasystems.

Many firms are trying to increase their flexibility to adapt to evolving patient needs and new products. Robots’ key advantage is that they can provide this flexibility, says Josh Russell, principal engineer in life sciences at Automated Systems of Tacoma. The vast majority of traditional filling machinery is dedicated to a specific container format, such as syringes, vials, or cartridges, and this design limits its capability. But robots integrated within an isolator–barrier system can fill–finish various container formats aseptically on a single modular system, says Russell. Robotic systems can minimize the operational and financial requirements for expanding filling capabilities and also enable facilities to be smaller and leaner.

Robotic filling systems also can help maximize equipment uptime because companies can change them over rapidly to another batch or product, regardless of container format, says Russell. Reconfiguring robotic systems requires few change parts, few process changes, and minor, if any, manual adjustments, unlike the changeover process for traditional filling systems. Robotic systems’ auto-adjust functionality manages production parameters and eliminates the need for operators to adjust the system manually.

To some observers, regulators seem to understand the advantages that robots can provide. “I don’t believe the regulators are standing in the way,” says Procyshyn. “If you come back to the regulators and say, ‘I can achieve a six-log decontamination. I operate at ISO 5 for particles, and I completed all of my validation media fills (and have the appropriate data to support this),’ the response from the agency is going to be, ‘OK. Sounds good to us.’”

“The future of aseptic manufacturing may come to rely heavily on robotic systems,” says Joerg Zimmermann, director of process development and implementation at Vetter Pharma-Fertigung. “Drugmakers are slowly abandoning the idea of discovering blockbusters and filling millions of units. Today’s clinical pipelines include many products that are highly specific to particular patients or patient subpopulations. These products will call for smaller batch sizes in production and more changeovers. Flexibility will become paramount, and robots will help manufacturers achieve it,” he says.

The regulatory atmosphere, current technology, and the characteristics of developing pharmaceutical products seem to favor industry’s adoption of robots for aseptic filling. “I don’t hear anyone saying that they don’t think robots are the future,” says Procyshyn. “The questions are how, where, and who, but it’s coming, for sure.”

Production Lines

The pharmaceutical industry has a history of developing innovative medicines and novel drug-delivery systems, but not all of its manufacturing processes use cutting-edge technologies. Demands to increase productivity in fill–finish lines are fueling the arguments of proponents of robotic automation to expedite manufacturing.

Robots' Role in Flexible Fill–Finish Lines

Q. I work in a quality control laboratory and use a pH meter with a single-junction reference probe to test samples taken from various pharmaceutical (drug) production lines. The probe I use has a six-month warranty. It slowly stops working after just a couple weeks. I am replacing it once a month. We make sure to store it correctly according to the manufacturer’s specifications and even use probe cleaner at the end of each shift to ensure that it stays clean. What can I do to increase the lifespan to at least cover the warranty period?

A. The most common problem seen with pH readings in pharmaceutical-drug testing is a progressively sluggish response. If a probe calibrates quickly but does not respond well in a sample or if it slowly quits working within a few weeks, it is most likely that the probe is not compatible with the sample. Single-junction probes are good for measuring weak ionic water-based solutions and drinking water. Because you are working with drugs, which are much more complex molecules, single-junction references are not suitable. There is nothing that can be done to prolong the life of a single-junction probe in this situation; they are simply not compatible.

Double and flushable junction probes are more appropriate for pharmaceutical applications because samples tend to be more complex. Large molecules will clog the single-junction probes over time. Thus, they may work well initially then become slow to respond over time. If a double junction probe is responding sluggishly, it simply may need to be cleaned. You can continue to clean the probe as you have (i.e., daily). Cleaning prevents proteins, fatty acids, and oils from building up on the glass and causing a delayed response. Proper cleaning and storage of probes is imperative for obtaining the longest life and their optimal accuracy.

If you encounter a situation in which the probe does not change the measurement values at all, the probe has probably shorted out. This happens most often during shipping or with rough handling. The wires used for the cable and reference are thin and somewhat fragile, and will give a steady reading if broken. We have also seen this happen often in production and manufacturing environments.

—Jennifer Minor-Newton, technical application specialist for Cole-Parmer

Troubleshooting

I work in a quality control laboratory and use a pH meter with a single-junction reference probe to test samples taken from various pharmaceutical (drug) production lines. The probe I use has a six-month warranty. It slowly stops working after just a couple weeks. I am replacing it once a month. We make sure to store it correctly according to the manufacturer's specifications and even use probe cleaner at the end of each shift to ensure that it stays clean. What can I do to increase the lifespan to at least cover the warranty period?

Equipment and Processing Report-01-18-2012

Common Equipment-Design Pitfalls That Impair Cleaning

January 2012 Editor's Picks: Products from ACS Valves and Terra Universal

Robots' Role in Flexible Fill–Finish Lines

Increasing the Life-Span of a Probe to Cover a Warranty Period