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Analytical tools and methods that require less water and detergent are gaining interest for faster, more efficient cleaning.
Cleaning verification of manufacturing equipment is one of the most critical parts of drug production. Be they residues from active ingredients or contamination from cleaning agents, manufacturers must ensure that trace amounts of material do not carry over from one batch to the next. Cleaning specialists have long debated issues such as the most effective cleaning techniques, how to evaluate the cleaning process, and even the very boundaries of what constitutes clean. Whether you prefer automated washing systems, combine manual and automatic washing, or just use old-fashioned elbow grease, there are infinitely varying opinions about what's clean, what isn't, and what are the best methods to ensure equipment meets cleaning specification.
To further complicate the issue, cleaning verification is often associated with complicated standard operating procedures and much downtime, which adds up to wasted time and money. And, it's impossible to be 100% sure that a piece of manufacturing equipment is clean.
"It's always about, 'Did you pick the right residues to look for? Did you pick the right analysis to look for it? Did you pick the right levels to look for it? Did you pick the right spot to look for it?' All of those risk-based issues come into play," notes Rebecca A. Brewer, director of consultation, validation, and good manufacturing practices compliance at the Dober Group (Midlothian, IL, www.dober-group.com).
To make cleaning processes and verification more efficient, companies are developing more effective, more efficient cleaning techniques and better analytical methods to ensure that residue levels are below predetermined acceptance criteria.
"I think that's the big thing people are looking for," noted Mary Thomson, PhD, director of applications at Remspec (Charlton, MA, www.remspec.com). "They want to eliminate some time from the cycle and reduce the number of steps required to do the cleaning validation because then, you cut down on the opportunities for errors to creep in."
A hallmark of new techniques is to bring traditional analytical tools online to accelerate and simplify cleaning verification and to improve cleaning results. Drawing increased interest are ion-mobility spectrometry (IMS), surface analytical devices, remote inspection devices, and cleaning technologies that require less water and detergent.
Online tools do the dirty work faster
High-performance liquid chromatography (HPLC), total organic carbon (TOC) methods, and other analytical tools have been standard parts of the cleaning validation process for decades. But to a certain extent, these methods are limited in speed and precision. For example, a typical HPLC analysis can take as long as 30–60 minutes to run and then even longer to analyze test results. And, the column replacement and mobile-phase costs of waste disposal can add up quickly. TOC provides nonspecific information about how much organic carbon is in a sample and can't identify the source of the carbon.
Though HPLC and TOC are valuable tools for some cleaning verification processes, companies are recognizing that other analytical tools have the potential to accelerate cleaning validation and make immediate decisions about cleaning. Says STERIS's (Mentor, OH) manager of technical services, George Verghese, "The US Food and Drug Administration's Process Analytical Technology (PAT) initiative, an effort to facilitate more efficient manufacturing and an integrated approach to quality assurance, has led to the exploration of in-line monitoring and measurement."
Spectroscopic methods. Much in the spirit of the PAT movement, analytical technology specialists are bringing ion-mobility spectrometry (IMS) and ion-trap mobility spectrometry (ITMS) at- or near-line to reduce sample analysis downtime. Though IMS isn't new—the security industry and the military have used IMS for years to detect narcotics and explosives—many observers see these instruments as part of an emerging trend to verify cleaning online without disrupting production processes.
IMS works by measuring how fast ions move through a gas to a detector under the influence of an electric field (see Figure 1) (1). Cleaning specialists are touting its advantages: analysis can be performed in as little as 10 seconds, the method produces little waste, no columns or mobile phase are required, and instruments can be manufactured small enough to be portable. "In theory, you can take the instrument to the piece of process equipment that you're using and make the measurements there," explains Derek Brand, global product manager at GE Sensing, a developer of such technology (Billerica, MA, www.gesensing.com).
According to Brand, ITMS and IMS are highly suitable for identifying small-molecule compounds and for raw material identification in quality control (QC) applications. "When using ITMS for cleaning validation, the instrument can use the same extracted sample that would be used for HPLC measurements. This would allow the use of the same swabbing and extraction procedure, only with a different (and faster) analytical technique." For QC testing, there is little or no sample preparation. A broken tablet can be wiped along a sampling trap and inserted into the instrument without any complex solvents.
With additional advancement, IMS and ITMS may also be able to help achieve direct swabbing, in which a technician could sample the wall of a piece of equipment and insert the swab into the instrument to get a direct reading at the line. This would clearly reduce production downtime and shorten the loop for analytical testing. There are some disadvantages—or, at least, some departures from current general practice. Most extraction tools can be reused, for example; direct-sample swabs cannot.
But one critic of the technology says despite these advances, the method still may not be ready for implementation from an operational standpoint. "The overall turnaround time is very short, but online detection may not be as reliable as the off-line determination," he says.
Mid-infrared fiber optics. Spectrometers equipped with infrared (IR) fiber optics can also detect surface residue without disrupting production. Says Dober's Brewer of this method, "It's one of the first in a number of techniques that I could see in the future getting the swab and the rinse out of the picture and detecting the soil directly on the surface of the equipment."
One example of this technology is Remspec's "SpotView" grazing head that can be used with a Fourier-transform infrared device to detect surface residue in real time. "Compare it with the TOC method, which just tells you how much carbon compound you have there. Because we're using infrared spectroscopy, we can tell one compound from another. We can tell you if you have the active material or excipients or detergents or a mixture of those," says Thomson. "If you think about it, that's the right way to tell if the surface is clean."
IR surface analyzers detect the thickness of coatings caused by as little as a few micrograms per square centimeter on reflective materials such as metal. The head delivers mid-IR signals to the surface and returns it to the on-board detector at the grazing angle for maximum sensitivity (see Figure 2). Thomson estimates that the instrument can perform analysis within 30 seconds.
According to a recent study of the technology by researchers from Novartis Corporation (East Hanover, NJ, www.novartis.com), the mid-IR fiber optics probe can effectively detect small amounts of contaminants on metal surfaces with loadings below 1 mg/cm2. But, the researchers also found that the probe could benefit from some additional modifications to accommodate curved surfaces (2).
Remote visual inspection. Reducing the time it takes to verify that vessels and tanks are clean has been another focus of cleaning specialists. Because the cleaning validation of these pieces of equipment often necessitates the use of a riboflavin (or vitamin B12) followed by human entry for inspection, remote visual inspection with borescopes and cameras could save time. "They let us look around in places that were previously not open to us from a visual inspection standpoint," says Brewer.
According to Sue Shields, product manager at GE Inspection Technologies' Everest RVI Technologies, a company that specializes in this technology, "Data show that every hour a pharmaceutical vessel is open costs the company about $1500 . . . Companies are really looking for ways to improve that manpower inspection."
Remote inspection works by placing an ultraviolet light source inside a tank after it's been cleaned. The riboflavin solution glows in places where it wasn't rinsed off, thus indicating whether surfaces are properly clean. Still and video cameras can capture images from inside that can be viewed from a remote location. Images can be stored for comparison or for documentation.
One criticism leveled at all of these analytical tools is that they fail to analyze the entire piece of complex equipment within a reasonable amount of time and only detect discrete sampling locations. Discrete sampling leads to many hard-to-answer questions such as where to sample, how much surface to sample, and how to recover the sample. "The most innovative analytical method is only as good as how you recover and bring sample to the analyzer," noted Steven A. Weitzel, director of validation and compliance at Novaflux Technologies (Princeton, NJ, www.novaflux.com). For these technologies to be truly useful in the industry, he says, they must have the ability to sample entire chains of equipment (or at least entire pieces of equipment) instead of relying on a few sampling locations.
Cheaper cleaning: less water, less detergent
Cleaning technologists have pinpointed another way to improve efficiency: reduce water and detergent use. For cleaning processes that use expensive purified water or water-for-injection, using reduced amounts of water could lead to a much cost savings.
Novaflux, one company working in this area, believes that rather than flooding a surface with liquid, a stream of gas (typically filtered, compressed air or inert nitrogen) carrying liquid droplets could be used. "These liquid droplets travel and impact the surface to be cleaned at high velocities and have a much better extraction efficiency to remove residues," explains Weitzel. Mass flow rates and velocities are adjusted so that the droplets that constantly impact the surface. "The two-phase flow technology changes the paradigm of cleaning. The droplet takes the contaminant out and forms another droplet until the surface is clean," says Novaflux's President Mohamed Labib. The two-phase cleaning technology has been validated for use in pipelines, membranes, and enclosed passageways.
Labib and Weitzel believe that the two-phase flow exposes contaminants to the smallest amount of liquid to accomplish thorough cleaning. The major advantage, they say, is that you can get at least 100 times more shear stress from droplet impact onto the surface during two-phase cleaning. Thus, adhering contaminants can be removed more easily than with traditional methods and with less water.
Because Novaflux's technique enables droplets formation and reformation in the two-phase flow, the technique is particularly helpful for targeting hard-to-reach areas such as pipes. In contrast to liquid-only cleaning with which the liquid boundary layer adjacent to the surface limits cleaning to passive diffusion and transport, the Novaflux technique directly affects the contaminated surface with a new form of hydrodynamics and transport process. Though the technology has been proven effective for medical device applications, Novaflux is working to perfect its use for the pharmaceutical industry.
Along the same vein, detergent manufacturers agree that it's important to use free-rinsing cleaning agents for better efficiency. Says Verghese of STERIS, "The rinsibility and drainability of cleaning agents can have a significant impact on the overall time, cost, and efficiency of the cleaning process, particularly when large surface areas and high-purity rinse water are involved." Factors such as the cleaning chemistry, toxicity, amount of foam generated, and cleaning process parameters are important.
But using less detergents overall also is important. To accomplish this, some cleaning validators are applying conductivity sensors to determine which chemical concentrations produce the best results and to gauge the quality of the cleaning. Conductivity sensors have traditionally been used in CIP applications to verify the completeness of the rinse; low-conductivity rinse water—at or near the level of the source water—indicates effective cleaning.
Rather than using a fixed amount of cleaning solution such as the standard 2% chemical concentrate equation, companies are using this tool to determine chemical strength, and quantity of cleaning agent required. Says Chris McNulty, pharmaceutical/biotech product manager for Sani-Matic, Inc. (Madison, WI, www.sanimatic.com), "We're seeing more people accepting the fact that they can actually use the conductivity analyzer to put in the required amount of chemical. If you have a process that's very dirty, the conductivity analyzer will put in more chemical as it's consumed, as opposed to trying to pick a worst-case scenario. If you clean something that's not very dirty, and it only requires a gallon to get the same chemical strength, then so be it." In the long run, he notes, companies will use only the amount of cleaning agent required, thus producing a more efficient cleaning method.
Process operators are also learning to use smaller quantities of application-specific detergents rather than large quantities of general-purpose cleaners. According to Art Vellutato, Jr., vice-president of technical support operations at Veltek (Malvern, PA, www.sterile.com), one-kind-fits-all detergents can require numerous application to remove residue. "Firms are looking for people to develop cleaners that actually attack the residue and are more aggressive cleaners for a specific residue," he says.
During the past several years, equipment manufacturers have increasingly tried to develop and market equipment that's cleanable with CIP operations. By definition, CIP technology offers complete cleaning in place without the need for additional manual cleaning. Whereas items such as totes and material bends are fairly easy to clean with CIP technology, the industry is now realizing CIP may have limitations with complex equipment such as tablet presses and is now moving to a new kind of CIP–wash-in-place (WIP) combination.
"I think customers have realized that it is difficult to achieve a total CIP situation," observes Ryan Keefer, sales and administrative manager at Elizabeth-Hata International (North Huntingdon, PA, www.eliz.com). From a validation standpoint, a final clean (or wipedown and swab) usually is needed before the next batch can be started.
Reinhard Sievert, general manager at L.B. Bohle (Warminster, PA, www.lbbohle.com), agrees that complete CIP is hard to achieve. "Real CIP cleaning systems, depending on what kind of process it is, can be very tough or nearly impossible. You can get close to it, but 100% CIP is almost impossible. That's rarely required most of the time."
"When you're looking for the isolation of a hazardous material or something that's very difficult to clean, it seems the industry is not just trying to achieve WIP, but a contained, isolated WIP," says Keefer.
According to Keefer and Sievert, this kind of cleaning can be achieved through containing a tablet press, for example, and isolating the accessories outside of the machine in a barrier–isolator where they can be washed in place. "That seems to be where the industry is going—with a little twist in what might be referred to as a CIP. It's going further than WIP, but it's not completely achieving CIP," Keefer says.
The pharmaceutical industry has a reputation for being conservative and prone to taking a long look at new technologies before being willing to integrate them into its processes. The cost and time required to change existing, FDA-approved processes are enough to deter many companies from adopting a new cleaning method.
Most industry observers agree that innovation in cleaning technology is not about convincing companies to overhaul their preexisting techniques and adopt new ones. Rather, it a matter of reevaluating old methods and combining them with new techniques to speed cleaning and cleaning validation. Using visual inspection in conjunction with a surface analyzer could be effective, for example. No single tool will solve all validation problems, but combining the best of new and old methods for a given process will most likely be the cleanest path for improvement.
1. K. Payne, "IMS for Cleaning Verification," Spectroscopy 20 (Suppl. The Role of Spectroscopy in Process Analytical Technologies"), 24–27 (2005).
2. N. Teelucksingh and K. Bal Reddy, "Quantification of Active Pharmaceutical Ingredients on Metal Surfaces Using a Mid-IR Grazing Angle Fiber Optics Probe—An In-Situ Cleaning Verification Process," Spectroscopy 20 (10), 16–22 (2005).