As an undergraduate, Barbara and her fellow biology and chemistry majors regularly sampled prototype cookies courtesy of the dad of a classmate; he was a formulator for a large commercial baker. The prototype cookies were invariably far superior to the final product. Issues arise in moving from R&D to large-scale production, and problems can be averted by using a pilot program. However, the pilot program itself has to be well-designed.
Pilot programs are useful in development of pharmaceuticals, cosmetics, nutritional supplements, medical devices, and aerospace components. In critical and precision cleaning, we often suggest that one way of hedging your bets is to set up a pilot plant before making a large commitment in new capital equipment. We suggest you purchase or lease smaller-scale cleaning equipment and use that equipment for cleaning process development.
Managing a pilot program involves many cleaning and contamination control challenges. In most instances a pilot plant is one where process equipment is used for many types of product. Therefore, equipment must itself be cleaned between projects. A pilot program is larger than bench-scale research and smaller than production. While there is often a limited budget, there are usually high expectations, time constraints, and pressure from management and marketing. There can be false perceptions that pilot programs don’t require much care, and there may be pressures to just put something together because it’s only temporary. Here are five potential tripping points, all related to precision cleaning, critical cleaning, undesirable residue, and contamination control.
Soil is matter out of place; a benign ingredient in one pilot study may interfere with product produced in a subsequent pilot study. People involved in pharmaceutical and related manufacturing are concerned about reducing the API (Active Pharmaceutical Ingredient) or AI (Active Ingredient) to an acceptable level. The API is the part of the formulation that is biologically active. However, given the range of products being produced in pilot programs, it is important to consider API as well as all potential interfering residue, whether or not it is biologically active.
The problem of residue is universal. For example, in metal fabrication and finishing, fine metal particles from one application can interfere with subsequent production. This interference can include particulate contamination and galvanic interaction. In precision optics, many manufacturing professionals deem that dedicated equipment, even for a pilot study, is a must.
Residue can be liquid, gas, or solid. Where the product is a powder, the program for residue removal depends on the situation. Equipment manufacturers sometimes recommend vacuuming to remove dry powder. However, such an approach may not adequately remove the contaminant, particularly if the equipment is to be used for disparate processes. In addition, sometimes the residue is not quite a powder that can be readily dusted off or vacuumed away. Instead, the residue may be an emulsion or a caked-on material, what critical cleaning professionals term a dreadful mess. Fine particles are particularly adherent, as they can be retained in areas of surface roughness; even what appears to be a smooth surface may have enough microscopic roughness to hold tiny particles. One logical strategy is to remove as much of the powder as possible without liquid, then resort to traditional CIP (Clean in Place) and/or COP (Clean Out of Place) processes using cleaning agents and processes including immersion, agitation, and ultrasonics.
Things change during scale-up. For example it was recently reported that during scale-up of what was considered a relatively straightforward formulation, even using careful process controls, process times had to be increased from 50 to 70 minutes.1 Process parameters may need to be reevaluated yet again in moving from the pilot process to full production.
Unexpected reactivity can be damaging. A highly-exothermic reaction can pose a safety hazard to workers and to the product. Other forms of reactivity include unexpected precipitation of residue in a liquid process bath, cleaning bath, or reactor. It is prudent to remove such residue before using the same equipment for subsequent pilot studies. As important, figure out the root cause of the precipitation. Just as in cooking, unexpected residue in the pilot program can be a sign that the process technique needs refinement. Even with extensive written instructions, important details can be lost. Therefore, consider paying a visit to your research group and observing as the process is performed. With such an approach, perhaps the production versions of the prototype cookies Barbara sampled at college would have been tastier.
Ideally, process equipment should be dedicated to a narrow range of applications. In reality, equipment in a pilot lab may be used for many different applications. For example, the equipment may be used for applications ranging from ingestible to industrial/janitorial products.
Even if great care is taken to clean promptly and appropriately, there may be applications where the risks of using pilot plant equipment outweigh potential benefits. When this happens, there are several strategies. One is to use disposable equipment in such areas as transfer lines. Where the risks are high, rather than use cleaning equipment where the residue is variable and may not be well-defined, it may be preferable to purchase new vessels or process baths, turning to restaurant supply stores, if necessary. Of course, it is important to verify that materials of construction of the process equipment is compatible with the product.
Shared controlled environments
When part or all of the process needs to be performed in a cleanroom or controlled environment, additional challenges can arise. Ideally, a small cleanroom or controlled environment would be dedicated to pilot programs. In such instances, the cleanroom itself is likely to require additional cleaning between pilot programs. Attention may be needed to the impact not only of particles but also of airborne molecular contamination (AMC).2 In addition, cleanrooms are expensive to build and to operate; it may not be feasible to devote a cleanroom to pilot programs alone. This means sharing. It can be difficult to schedule use of an existing production cleanroom for a pilot project, and even then, extra care must be taken to assure that the pilot processes do not interfere with production activities.
Results of a pilot program often lead to a “go/no go” for a new product. Planned carefully, pilot programs bridge the chasm between R&D and production and become a critical point in the value chain. Taking the time to assure that the pilot program emulates expected production conditions can avoid costly headaches.
In addition, no one wants to discard a good product or process due to apparent poor performance in the pilot program when the problem was actually due to inappropriate cleaning and contamination control. Therefore, we advise people who are told to hurry up and do the pilot runs to think of the demands as being tailgated on a winding road. Don’t speed up and don’t stop; but slow down and consider the cleaning and contamination control challenges.
1. Haack, D. and M. Koberle, “From Bitter to Sweet: Developing a User-Friendly Painkiller, Pharmaceutical Technology, Dec. 26, 2016, p.26
2. Kanegsberg, B. and E. Kanegsberg, “Airborne Molecular Contamination Part 2: Head It Off,” Controlled Environments, September 2009. http://www.cemag.us/article/2009/07/airborne-molecular-contamination-part-2-detecting-amc
Barbara Kanegsberg and Ed Kanegsberg (the Cleaning Lady and the Rocket Scientist) are experienced consultants and educators in critical and precision cleaning, surface preparation, and contamination control. Their diverse projects include medical device manufacturing, microelectronics, optics, and aerospace. They can be reached at email@example.com.