	This article will address common mistakes that impede the effectiveness of automated washing of, for example, laboratory glassware or manufacturing equipment parts.  When establishing an effective cleaning program, it is important to consider industry-accepted cleaning factors, which include temperature, action, chemistry, and time (TACT), as well as coverage and soil. To appropriately account for these factors in an automated washing system, one must select appropriate chemistries and loading accessories. In addition, there are several common mistakes that can be avoided.

 If hot water is used at the prewash phase when attempting to clean a protein-based soil, the soil will “bake” onto the surface, which will make it difficult to remove during the subsequent wash phase. The solution is to use cold water in the pre-wash phase when cleaning a protein-based soil. 

 Using cold or ambient temperature water during the wash phase when attempting to clean oily or greasy soils will either increase cycle time or fail to remove the soil from the surface. When working with these types of soils, very hot water should be used in both the prewash and wash phases of the automated washing process.  While it is important to monitor the water temperature during prewash and wash, when cleaning greasy soils it is also important to consider temperature during the final rinse phase. Performing the final rinse of the automated washing process with very cold water will lead to long drying times. It is optimal to use the highest possible final rinse temperature. 

 Consider the appropriate operating range of water temperatures for the chemical being used to remove the soil. Check the manufacturer's label on the cleaning chemistry for the recommended water-temperature operation range to ensure timely and complete removal of a soil. The chemical's pH is also crucial. Using chemicals with the wrong pH can result in either a long wash time or improper cleaning. It is best to use acidic chemicals for inorganic, mineral-based soils and alkaline chemicals for organic and protein soils. It is also important to remember that certain types of process parts or load items might be pH sensitive. Acidic or alkaline detergents used to clean aluminum parts or load items, for example, can lead to accelerated degradation or deterioration of those item surfaces. When working with these types of substrates, the best results will usually be achieved by using a pH-neutral chemistry. 

	Wash times may be extended if using a lower detergent concentration for items that are heavily soiled. In this instance, the detergent concentration should be increased until a reasonable result/time ratio is reached.

	While it is important to ensure appropriate detergent concentration, it is also mandatory to consider the impact of chemistries that will create foaming in the chamber. Foam will create cavitation or the formation of vapor cavities in a liquid in the pump, which can lead to lower water pressure and potential damage to the pump. Foam can also negatively impact sensors and probe readings. Foam can also increase the required volume of rinse water needed to complete the cleaning process. To avoid these issues, it is important to use the wash temperatures and chemicals recommended by the equipment  manufacturer. Non-foaming detergents can also be used. 

 The rinse phase is yet another area where mistakes can increase overall cycle time. Setting a long time for a rinse phase will result in a longer cycle time and lower efficiency. It is best to shorten overall rinse time and to simply add additional rinse phases. In addition to reducing the time for rinse phases, it may be helpful to reduce the rinse temperature to prevent stress on equipment. High temperature does not equate to improved rinsing efficacy. There are certain applications, such as animal cage processing, where thermal disinfection is required, and for these the rinse temperature in all phases must remain high (1).

 Water quality is crucial to a successful automated washing process. In instances where low quality water is used in all phases, spotting, increased detergent usage, and overall poor cleaning performance may be encountered. It is recommended that the washer supplier’s water quality recommendations be followed. Water hardness must also be considered. Hard water will often require a higher concentration of chemicals. At a minimum, using mineral-free water such as reverse osmosis, deionized, distilled, or water-for-injection water in the final rinse phase will likely improve the cleaning efficacy. Another option is to add a formulated acid cleaning agent second wash following a primary wash phase. 

 The positioning of load items and/or overloading baskets can create problems in the cleaning process. If items are positioned incorrectly, they may receive inadequate coverage and as a result will not be fully cleaned. It is imperative to follow the washer supplier’s recommendations for the positioning of components within the loading racks. For example, 

shows how to use a clip on a spindle rack. Overloading the basket, as shown in 

, may also result in poor coverage or inconsistent cleaning results. Overloading should be avoided to ensure optimal cleaning. 


	1. C.L. Wardrip, J.E. Artwohl, and B.T. Bennett, 

Contemp. Top. Am. Assoc. Lab. Animal Sci.


	Olivier Van Houtte is product manager, Life Sciences Washing Systems, at Steris, 

	Please cite this article as: O. Van Houtte, "Preventing Common Mistakes in Automated Washing," 

Articles

Troubleshooting

Careful choice of wash-water parameters and attention to water quality and basket loading are important for optimal cleaning.

Tips for Automated Washing

	Creating a quality culture is a worthwhile goal for any pharmaceutical company and is supported by FDA, which wants companies to aim for "right first time". Microbiologists can play a role by helping to prevent microbial contamination incidents, rather than just investigating them after they occur. By getting involved, the microbiologist can shift the focus from compliance to quality, noted Karen Ginsbury, founder and CEO of PCI Pharmaceutical Consulting Israel and chair of IVT's Microbiology Week, in the conference's opening remarks on June 2, 2015. The cost of non-compliance is high, added Ginsbury, pointing to some recent problems related to contamination and environmental monitoring practices called out in warning letters this year. Facility design, cleaning strategies, and using investigation findings to fix problems at the source, however, can prevent microbial growth and create quality in both sterile and non-sterile manufacturing.

	Monitoring and then analyzing the resulting data can reveal problems in the making. "You may not have exceeded action levels, but if you find a discrepancy when you compare data in different production areas and compare these to historical data, you can take action anyway, such as running an extra cleaning cycle," urged Ginsbury. In the case of a contamination event, "You should 'reconstruct the crime scene' to find out what went wrong. A single root cause is seldom found, because there are often multiple contributing causes. You should fix these and then monitor further," she added.

	Monitoring and preventing contamination in a non-sterile (i.e., controlled, non-classified) process, in which limited but controlled bioburden is allowed, is actually more difficult than in a sterile or aseptic process, in which no bioburden is allowed, because aseptic processes have more stringent controls, said Chris Knutsen, associate director of analytical and bioanalytical development at Bristol-Myers Squibb, in a presentation at the conference. Crucial areas for microbial control in non-sterile manufacturing include incoming materials (e.g., APIs and excipients), personnel, and water. "Standing water is a common source of contamination in non-sterile manufacturing," said Knutsen. "Water organisms grow easily and can form a biofilm that is difficult to clean. A common problem, for example, is hoses that are stored with water trapped in them."


	Operators of non-sterile processes now have more specific directions to follow, since in 2014, USP published an informational chapter, 

 <1115> "Bioburden Control of Non-sterile Drug Substances and Products," which details risk assessments and environmental monitoring for non-sterile processes. Prior to this publication, operators of non-sterile processes sometimes used 

 <1116> "Microbiological Evaluation of Clean Rooms and Other Controlled Environments," which is an informational chapter for aseptic processes.

	In February 2015, the European Medicines Agency published a concept paper describing a revision of Annex I of the EU GMPs, which will include updates for sterile processing and adaptation to International Conference on Harmonization Q9 and Q10 documents. The revision will also specifically address non-sterile processes, noted Ginsbury.

	A Parenteral Drug Association (PDA) publication, planned for publication in 2015, is a technical report on cleaning and disinfection, said Jim Polarine, technical service manager at Steris, who serves on the task force for this report. In a conference presentation, he described components of validating disinfectants for a cleanroom. Vendors will test efficacy of disinfection against ATCC standard reference organisms, but ideally, users should test in-house environmental isolates. First, the cleanroom should be monitored for six to twelve months and organisms should be identified. From these data, isolates can be chosen for 

 testing. Knowing what flora are normally present in a facility is crucial. If something changes-a new floor, for example-the disinfection program should be revalidated, said Polarine.

	Polarine also discussed best practices for disinfection, which include ensuring appropriate contact time and testing the effect of water quality on the disinfectant. It is possible to have too much of a good thing, however. Over-use of sporicides can break down flooring or wall materials, and these damaged surfaces create places for microbes to grow, noted Polarine. Some sporicides can cause corrosion; when this occurs, the corroded part should be replaced or monitored for microbial growth.

	More discussions on these and other topics will be discussed at IVT's Validation Week in Philadelphia, Oct. 27–29, 2015. 

Production Trends

Presenters at IVT's Microbiology Week discussed best practices and recent guidance publications for microbial control in sterile and non-sterile pharmaceutical processes.

Microbiologists Contribute to a Quality Culture

	The US Drug Supply Chain Security Act (DSCSA), and how pharmaceutical companies can meet its serialization requirements, has been at the top of many agendas since the first phase of the law, which requires change-of-ownership data, came into effect in 2015. A crucial question is whether to implement the requirements in stages (i.e., to meet the machine- and human-readable package-code requirements for November 2017) or to look at the end goal of unit-level track and trace that will be needed in 2023. Implementation-even of today's requirements-has many technical and organizational challenges, and few companies are looking ahead, said speakers at a session on serialization at INTERPHEX 2015 (1). Companies would benefit, however, from a more holistic view, noted Joe Whyte, global serialization lead for Rockwell Automation, in a seminar on May 20, 2015 (2).

	"Looking at serialization piece by piece is inefficient and problematic because you need interoperability between all system levels for traceability," said Whyte at the seminar. "Companies shouldn't look only at legislation requirements. Instead, they should look at the business benefits and do the whole traceability project now." Benefits of traceability include real-time visibility into what consumers are buying, which allows businesses to optimize their inventory and production levels. Additional benefits include the opportunity for patients who voluntarily choose to share information with the manufacturers of the products they use to participate in patient support, patient compliance, and patient safety programs (e.g., individual notification of recalls). These benefits are being realized in other industries, such as consumer products and groceries, Whyte pointed out, noting how shoppers today receive targeted coupons at the grocery checkout based on the barcodes of their purchases, for example.

	While most countries have serialization laws, most are not yet requiring aggregation and traceability, with the exception of Brazil. "Brazil is the pilot project for the world on aggregation and traceability," said Whyte. Brazil is on the most aggressive timetable, with full traceability required by the end of 2016 and a proof of principle by the end of 2015, for which companies must test traceability of three batches of one product all the way from the manufacturing plant to the consumer. Once Brazil has a completely traceable system with more secure products going to consumers, other countries are likely to implement sooner than legislative deadlines to stay competitive, predicts Whyte.

	The equipment needed for a traceability system is available now and is being used in Brazil already, Whyte said. There are, however, some challenges to address when implementing a system. Connecting equipment (e.g., printers and machine vision) is crucial; standard, open network and communication systems, rather than custom systems, facilitate equipment interoperability, which is more flexible and subsequently easier to support, noted Whyte. Storing and accessing data are other challenges that are optimally solved using cloud storage, said Whyte. "The customer standing at the drugstore counter does not want to wait long for data to be checked. Cloud storage allows for secure high speed data movement no matter what the geographic locations."

	Choosing a standard for sharing and communicating data is another issue. FDA's draft guidance on data exchange, released in November 2014 (3), allows use of electronic data interchange (EDI); EPCIS, an electronic product code system from GS1; or web portals. Many companies in the US have chosen EDI, but EPCIS, which was built specifically for track and trace, is more flexible and may be a better long-term choice, cautioned Bob Celeste, former senior director at GS1 US and founding partner of consulting company RC Partners, at the seminar (4). For example, EPCIS is a global system that allows queries, while EDI does not, he explained.

	Another aspect is testing the traceability system. Virtual systems are a useful tool for testing without the risks of testing a real system, such as a test product accidentally reaching a consumer, said Celeste. Using software, a company can test whether the traceability system works by, for example, introducing a counterfeit drug at some point in the supply chain and testing if and when it is noticed. Scenarios such as recalled product or theft can also be simulated. "Companies are responsible for serialization data and must use it to protect patients, not just collect and store it," noted Celeste.

Pharm. Tech. Sourcing and Management enewsletter

www.pharmtech.com/serialization-deja-vu-all-over-again

		J. Whyte, "Serialization Challenges-Holistic Solution & Support," presentation at the Serialization Seminar (Iselin, NJ, 2015).	

Draft Guidance for Industry: DSCSA Standards for the Interoperable Exchange of Information for Tracing of Certain Human, Finished, Prescription Drugs: How to Exchange Product Tracing Information 

		B. Celeste, "Serialization GS1 Standards," presentation at the Serialization Seminar (Iselin, NJ, 2015). 

Packaging

Although full traceability is not required by law in the US until 2023, companies could benefit from implementing it now.

Equipment and Processing Report-06-17-2015

Tips for Automated Washing

Microbiologists Contribute to a Quality Culture

Considering Full Serialization