Cleanroom Cleaning 101

By MaryBeth DiDonna

While filtration, special surfaces, and operating procedures establish and maintain cleanliness levels in a cleanroom, routine cleaning and maintenance are vital to keeping a facility clean. Inadequate or sloppy housekeeping can result in reduced product yields, compromised products or experiments, or higher operating costs.

Cleaning supplies and tools, including mops, buckets, and cleaning agents, should be matched to the cleanliness class of the cleanroom. (Photo: Perfex Corp.)
In a survey from the editors of Controlled Environments, representatives of companies that supply cleanroom consumables shared advice on cleaning practices, products, and strategies. They also discussed cleaning challenges and the advantages and disadvantages of using company employees to clean versus using an outside cleaning service.
Cleaning procedures
The procedure for cleaning a controlled environment will differ according to the individual company, the processes occurring in the clean facility, and cleanliness levels required. No matter the specifications, though, there are some universal steps to follow, the experts say. Each facility should have written standard operating procedures and checklists for different cleaning frequencies (by shift, daily, weekly, etc.).
David Nobile, senior technical services engineer from Contec Inc., Spartanburg, S.C., suggests some basic protocols that every facility should follow when establishing a cleaning procedure:
• Environmental monitoring (EM) and identification of contaminants (viable and/or non-viable).
• Select cleaning chemicals and disinfectants based on the results of the EM program.
• Select cleaning materials appropriate for the class cleanroom and the applications/uses.
• Determine that the materials selected perform as expected or required.
• Consult recommended practices for protocols and cleaning frequency from the Institute of Environmental Sciences and Technology (IEST).
• Write protocols based on the preceding information.
• Conduct cleaning verification tests.
• Revise protocols if necessary and re-verify.
• Train staff.
• Implement cleaning protocols.
• Self-audit to ensure protocols are followed.
Within a facility, different areas will require different cleaning strategies. Many variables must be considered. Baseline particle counts should establish the cleaning standard.

Eric Swainbank, sales and marketing manager for Terrell, Texas-based Degage Corp., identified three areas that require different levels of cleanliness. In gowning areas, cleanliness levels may be less strict, but the area will require more frequent cleaning. Frequent cleaning is also required in areas where products cannot be contaminated, but can transfer contamination. In production areas, cleaning must be done to the highest level.
"To establish a cleaning process and schedule, the above items need to be considered from the baseline test all the way down to the critically clean areas and the activities that take place in each one," Swainbank says.
Different levels, different demands
The methods, materials, and frequency may be quite different for cleaning a Class 1 cleanroom versus a Class 7 cleanroom.

Cleanroom cleaning can be labor intensive and require a range of cleaning agents and materials for different tasks. (Photo: Mar Cor Purificaton)
"The products used are vastly different in material and the method in which they are used," says Seb Russo, vice president of sales and marketing at Connecticut Clean Room Corp., Bristol, Conn. "Is it an aseptic or non-aseptic room? Is the process sensitive to cleaning chemicals? Does the room contain a process or is it just for testing? A knowledgeable cleanroom product distributor can help in determining what products to use."
Nobile says the methods for cleaning different environments are the same, or nearly so. The difference lies in the consumables used, and the frequency with which they are used. "As a general rule, the cleaner the environment, the more inherently clean the consumable," he explains. "As example, while a wipe made from polyester and cellulose fibers is suitable for an ISO 7 environment, it wouldn't be used in an ISO 4 environment, where pure synthetic wipes would typically be used."
While cleaner environments are typically cleaned more frequently, Nobile adds, this is not always the case. "A great deal depends on the activities within the environment and the various risks to the products produced within them."
"In Class 100,000—depending on the use of the room—you might be changing it and mopping the floors once a week," says Cathy Albano, marketing and sales manager for Liberty Industries, East Berlin, Conn. "In a Class 1 cleanroom—because of the protocol—it needs to be done after every shift or at the end of every day versus every week. The cleaner the cleanroom, the more you need to clean it to make sure that it stays clean."
For pharmaceutical facilities, U.S. Food and Drug Administration (FDA) and United States Pharmacopeia (USP) standards for disinfection establish cleaning protocols.

Airborne disinfection agents, such as peracetic acid, can be used to sterilize cleanrooms and aseptic areas. (Photo: Mar Cor Purificaton)

Developing effective, compliant disinfection procedures for the facilities is where the users of disinfectants sometimes get in trouble, comments Christopher Fournier, vice president of marketing at Mar Cor Purification, Lowell, Mass. He recommends that users follow the recommendations set forth by the USP 29 NF-24 <1072>, to get the correct efficacy, and to simplify the protocols. USP <1072> classifies biocides for cleanroom disinfection and provides definitions on decontamination techniques, the use of disinfectants, sanitizing agents, sporicidal agents, and sterilants. It outlines the factors affecting and the process of selecting an appropriate disinfectant for a pharmaceutical manufacturing environment.
When considering the risk versus the benefits, Fournier says, peracetic acid is one of the better choices for cleanroom disinfection and is being used by more biopharmaceutical companies.
Peracetic acid is validated as a sporicidal agent and sterilant, but is not toxic, carcinogenic, mutagenic, or hazardous. It can be used in very low concentrations (less than 1%), as a liquid for manual disinfection procedures, or in vapor form as an airborne disinfection agent in cleanrooms and aseptic areas.

The bare necessities
The supplies needed for cleaning a facility will vary according to the cleanroom's classification and purpose, but there are certain materials that every facility should use.

Shoe covers provide an important barrier against foot-borne contamination during cleanroom cleaning and normal room use. (Photo: Shoe Inn)
Cleaning a home requires a collection of mops, vacuums, wipers, and cleaning agents. Similarly, cleanrooms require different tools for different cleaning tasks. Wipes and swabs clean small areas; mops are dedicated to larger surfaces. Cleaning solutions should be formulated to the task. Vacuum cleaners, non-shedding mops, and sticky rollers are other necessities.
"All cleanrooms should have the basic materials used for wipe-downs, and floor and wall maintenance to follow the standards for each designation," says Russo. "This can only be answered by the classification and the process that is going on in the room."
Swainbank recommends several items that all cleanrooms should stock. "The must-have consumables to maintain cleanliness are non-shedding wipes, sticky mats, mops, HEPA filter vacuums, disinfectant sprays, cleanroom smocks, gowns, gloves and shoe covers, cleanroom trash bags, and trash cans," he says.
Since a cleanroom may have small corners and edges that can be missed when mopping floors and wiping down walls,  more specialized equipment sometimes is required.
"One thing that should not be overlooked when maintaining the cleanliness of a cleanroom is the importance of a swab," notes David Perkins, senior vice president of sales for medical and critical environments at Puritan Medical Products, Guilford, Maine. "Cleaning walls, floors, and other flat surfaces can give the appearance of a clean work environment but there are many nooks and crannies where the use of a swab is critical. The cleaning process should include areas that can accumulate particulates in hard to reach areas that only a swab can effectively clean."
Perkins identifies machinery and equipment, floor drains, and air handling systems as areas suitable for cleaning with swabs. In addition, swabs can be used to test for molds, bacteria, total organic carbon, and proteins.
Garments are an important tool in a cleanroom, especially to cover workers' feet so that particles are not tracked inside.
"Shoe covers are 'must-have' consumables in order to maintain cleanliness in a cleanroom. Out of everything people wear, shoes are by far the dirtiest and most likely to have things stuck to them that can fall off," says Jeff Foster, product manager for Shoe Inn, Sparks, Nev. "Moreover, according to one recent study, researchers found at least nine different types of bacteria on peoples' shoes. Shoe covers prevent these types of contaminants from entering and being left behind."

Hire a service, or DIY?
Who is best suited to perform housekeeping in a clean environment? Those that work in the cleanroom, a special in-house cleaning team, or an outside cleaning service? There are advantages and disadvantages to each, say cleaning supply representatives.
An in-house staff will be most familiar with the facility equipment and, since they are already employed by the company, it is easy to keep track of their progress. However, while the company employees may be specialists in the manufacturing, technical, or research work performed in the cleanroom, they may lack the skills and knowledge to properly clean the area. Adding cleaning responsibilities will reduce the amount of time available for performing assigned tasks. The lack of third-party verification is another issue.
"The biggest disadvantage of outside [cleaners] is lack of knowledge as to the machines, the chemicals, the equipment and the procedures," says Colleen Cole, Josco Products, Austin, Texas. "The best advantage is they will have a routine and follow it."
As for in-house staff, an advantage is that they are taking care of the area where they have to do their work, and as such they "take pride in their workspace and understand the material flow within that workspace," notes Perkins. "The downside to using in-house cleanroom staff is it can be easy to become complacent and usually the cleaning takes place at the end of a potentially long work day."
"In-house staff can be monitored and adjusted easily, while an outside service may have more experience," adds Mike Dougherty, sales and marketing, Perfex Corp., Poland, N.Y.
An obvious advantage of using in-house cleaning is cost, says Russo. While using and outside contractor would cost more, he says. "Contractual accountability, certification, and taking the guess work away from the company are advantages."
"The fact that cleaning cleanrooms is so difficult and underappreciated, it can also result in poor adherence to cleaning protocols and inconsistent results, whether done by direct employees or an outside contractor," says Sullivan. "But this condition is greatly exacerbated by a lack of sufficient supervision and high worker turnover that is not uncommon when using an outside cleaning service."
Cleaning contamination that cannot be seen is a challenge. The work can be difficult, especially when performed in garments, gloves, masks, and head coverings. The best strategies, the experts say, is to establish proper protocols, provide the proper cleaning tools, and communicate the importance of the housekeeping processes.
"This goes to the heart of the manufacturing operation: What do we (the manufacturer) make? Why do we make it in a cleanroom? What are the risks to our products? Why do we follow the cleaning protocols as we do? What is the impact of my role in all this?" says Nobile. "While these topics may seem a bit 'touchy-feely' and one might assume cleaning staff should know the answers to these questions, the reality is far different. Once knowledge and understanding of the need for cleaning is achieved, consistent and exemplary results are possible."
 

Applying the recommendations of ICH Q10 to statistical analysis can help prevent product recalls.

Aug 2, 2012 By: Lynn D. Torbeck Pharmaceutical Technology Volume 36, Issue 8, pp. 36-37

Lynn D. Torbeck

The International Conference on Harmonization ICH Q10 guideline, Pharmaceutical Quality System, and its two companion guidelines Q8 Pharmaceutical Development and Q9 Quality Risk Management, have been readily accepted if not fully implemented by the pharmaceutical industry over the past few years (1–3). Discussions of the statistical implications of Q8 and Q9 have appeared since theguidelines were harmonized (4). Little has been said, however, about the statistical content of the Q10 model, probably because it is perceived to be focused only on the management of the quality system. There are many Q10 recommendations that affect statistical issues facing the pharmaceutical industry, however, the guideline states that it is not "intended to create any new expectations beyond current regulatory requirements" (1). Although no new statistics or sampling plans are explicitly required by Q10, it goes without saying that current regulatory requirements are, in fact, mandatory. In addition, cGMPs continue to improve over time and according to Q10, "Implementation of ICH Q10 throughout the product lifecycle should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities" (1). That link should include the results of statistically designed experiments and related statistical and risk analysis.
While not explicitly requesting these approaches, ICH clearly implies that companies need to be proactive when it comes to corrective and preventive action (CAPA) programs. In today's environment, it is not sufficient to be reactive alone when problems occur. The Quality department must routinely seek out potential problems and prevent them before they result in rejects or recalls. For example, Q10 notes that companies should "Establish and Maintain a State of Control. To develop and use effective monitoring and control systems for process performance and product quality, thereby providing assurance of continued suitability and capability of processes" (1).
Having control over one's product and process is not a new expectation, although there is still confusion as to what a proper "state of control" means (4). It is not enough to ask for a state of control; the industry must provide and define additional modifiers. There are several ways in which a process can be in a state of control or, conversely, in a "state of out of control." A process can be in control, for instance, for financial and accounting, for regulatory compliance, and for organizational and managerial control. These forms of control are usually assumed to be in place. There are two other states of control that are germane to statistics: engineering and statistical.
A process is said to be in a state of engineering control when the process can be changed and adjusted using control knobs and/or by setting the critical process parameters (independent variables) that affect the dependent responses (5). When in control, the product always meets its specifications even if inconsistent and erratic. Time plots with specification lines are used to monitor the process. A process is said to be out of engineering control when it fails to meet its specifications.
A process is said to be in a state of statistical control when the process has been designed, developed, and adjusted to produce product that, while still containing some variability in the critical quality attributes (dependent variables), is predictable in that variability over time. Statistical control charts are used to monitor the process. A process is said to be out of statistical control when it fails one or more of the eight Western Electric control chart rules (6). As Q10 notes, "The pharmaceutical quality system should include the following elements, process performance and product quality monitoring, corrective and preventive action, change management, and management review" (1).
Product quality monitoring can be interpreted as trending the critical quality attributes. Again, proactive CAPA is preferred to reactive CAPA. As Q10 highlights: "Advocate continual improvement" (1). This continual improvement should include proactive variability reduction. Also recommended in Q10 is: "... a written agreement between the contract giver and contract acceptor." This agreement should include the acceptable quality limit (AQL) and limited quantity (LQ) limits for incoming sampling plans as well as the usual specification methods and acceptance criteria. Data collected in-coming and in-process can be used to determine compliance with a contract agreement. Per Q10, "Throughout the product lifecycle, companies are encouraged to evaluate opportunities for innovative approached to improve product quality" (1).
There are many ways, statistically, to achieve this goal. Trending, designed experiments, variability reduction, and design space are just some of the tools that can be used to make process improvements.
Many of the terms in ICH Q10 imply trending of critical parameters and attributes. It is a given that this must be done. Q10 states: "An effective monitoring system provides assurance of the continued capability of processes and controls to produce a product of desired quality and to identify areas for continual improvement" (1).
Process capability is measured by comparing the variability of the product/process to the width of the specification range. This comparison can best be achieved using statistical tolerance intervals because they take into account the sample size where Cpk and Ppk do not. Per Q10, "Identify sources of variation affecting process performance and product quality for potential continual improvement activity to reduce or control variation" (1). Some Six Sigma programs have gotten a poor reputation in certain circles because of a single-minded focus on saving money as opposed to giving equal consideration to improving quality and reducing variation. It is the author's opinion that management needs to give equal attention and resources to both. As Q10 calls for, "Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs and Medical), to ensure the change is technically justified" (1). The company's statistics department or a statistician should be included in the team.
Many statements in ICH Q10 have important implications for the correct and consistent use of statistics in the day-to-day implementation of pharmaceutical quality systems. Addressing these harmonized recommendations proactively and in context can help to strengthen one's quality system and thereby reduce rejects and recalls.

References and notes
1. ICH, Q10 Pharmaceutical Quality System (2008).
2. ICH, Q8 Pharmaceutical Development (2009).
3. ICH, Q9 Quality Risk Management (2005).
4. L. Torbeck, Pharm. Technol. 35 (10) 46–47 (2011).
5. Note: Other definitions of Engineering Control exist in other industries.
6. Note: It is common practice to use only one to three of the eight Western Electric rules for a given control chart. It is counterproductive to use more than three rules at a time.

Inside USP: US Pharmacopeia Proposes New Standard on Glass Quality

US Pharmacopeia documents best supply-chain practices and seeks broad input on proposal.

Jun 2, 2012 By: Anthony J. DeStefano, PhD, Desmond Hunt Pharmaceutical Technology Volume 36, Issue 6, pp. 68-70

During the past two years, the growing problem of glass particles in injectable medications has led to a number of product recalls. The crux of the problem is the durability of glass containers. Specifically, the inner surfaces of some glass containers are less durable and thus more susceptible to delamination (i.e., the shedding of glass flakes from the vial's interior walls) than others. Numerous factors may affect glass durability. Although the impact of glass delamination on patient safety remains a point of debate, the presence of these particles is at the very least a serious quality problem that must be addressed.
In a March 2011 FDA advisory to drug manufacturers on the formation of "glass lamellae" in certain injectable drugs, the agency noted that, although no adverse events had been reported at that time, there is the potential for drugs administered intravenously that contain these fragments to cause embolic, thrombotic, and other vascular events; and when administered subcutaneously, to lead to development of foreign body granuloma, local injection site reactions, and increased immunogenicity. Several conditions have been associated with a higher incidence of lamellae formation, including glass vials manufactured by the tubing process (and thus produced under higher heat); drug solutions formulated with certain buffers; drugs formulated at high pH; and drug products that undergo terminal sterilization. Based on the sudden increase in this occurrence and subsequent recalls, the US Pharmacopeial Convention (USP) Packaging, Storage, and Distribution Expert Committee developed a new general chapter that recommends approaches to predict potential formation of glass particles and delamination. The new informational chapter, General Chapter <1660> Evaluation of the Inner Surface Durability of Glass Containers, will be proposed in the July–August 2012 Pharmacopeial Forum (PF) and was posted in advance of its publication on the USP website in May 2012.
For the purposes of pharmaceutical packaging, three types of glass are defined by USP General Chapter <660> Containers—Glass. Type I (borosilicate glass) is suitable for most products for injectable and noninjectable use. Type II is treated soda-lime glass, and Type III is soda-lime glass on the basis of the hydrolytic resistance of the glass. Glass, in the form of ampuls, bottles, cartridges, vials and prefillable syringes, is the container material of choice for injectable products, particularly biopharmaceuticals.
Recent recalls underscore the fact that not all Type I glass is equal in terms of quality. Glass delamination, which ultimately results in the appearance of lamellae, is a lagging indicator of structural instability of a container. Although delamination is the most obvious visual indicator of instability, it represents the final stage of a seriously weakened glass surface structure, and can be observed only at a point where prevention is no longer an option. As such, proper evaluation of the quality of glass containers is crucial. Among the areas covered by USP's new informational chapter are:

• Good Glass Supply-Chain Practices: The chapter recommends steps for manufacturers in selecting a glass container vendor, including auditing the supplier, obtaining glass formulation from the supplier, designating formulation of Type 1 glass (33 glass or 51 glass), determining tubing glass source(s), and determining whether the containers have been treated with ammonium sulfate, among others.
• Glass Surface Chemistry: This section discusses use of the aqueous chemistry of surface glass to decide on the potential drug product formulation and treatment steps that could increase glass stability.
• Factors that Influence Inner Surface Durability: This section offers information on factors that have the potential to influence the durability of the inner surface of glass containers. These factors include glass composition, the conditions under which the containers were formed, subsequent handling and treatments, and the drug product in the container. The section notes that not all factors influence surface durability to the same extent, and their effects can be additive.

The draft general chapter also details screening methods to evaluate inner surface durability. These build upon General Chapter <660>. At present, each lot of Type I glass containers received by a pharmaceutical manufacturer must comply with the Surface Glass Test detailed in General Chapter <660>. Although this test provides an indication of the durability of the surface, it does not provide a direct correlation with the susceptibility to form glass particles or to delaminate. The most important variable that affects surface durability is the drug product itself (i.e., the interaction between the product and the container). The Surface Glass Test does not take the drug product into consideration. Therefore, as USP states in the general chapter, this test represents only the first step in quality control of surface durability, and additional screening methods should be employed.
Predictive screening methods help evaluate glass containers from different vendors, glass formulations, and post-formation treatments. The general chapter addresses the three key parameters that screening methods should employ as well as commonly used analytical methods for evaluating the three parameters. It notes that predictive tests should look for precursors that lead to delamination rather than flakes themselves, and should be able to quickly provide predicative indication of surface durability. The general chapter also details other testing that may be useful, particularly in evaluating interaction with specific drug products.

Formation of glass particles in injectable drug products represents a growing challenge. USP's new informational general chapter is intended to augment its current glass standards via recommended approaches for predicting the potential for this disintegration to occur. This may serve as a resource for manufacturers, and the organization is seeking input on its proposal

Clean-in-place systems should be optimized during design and commissioning and after validation.

A Lifecycle Approach to Optimizing Cleaning Systems

Dec 2, 2012 By: Andrew Wong, Cody Shrader Pharmaceutical Technology

(GLOWIMAGES/GETTY IMAGES)

In the 1990s, pharmaceutical manufacturing facilities started to adopt clean-in-place (CIP) technologies to improve cleaning processes and increase critical equipment uptime. While these early systems provided significant benefits over manual cleaning, they were assembled before more modern guidance on construction and optimization. Their designs have subsequently been propagated to other production facilities without significant re-evaluation. As such, cleaning cycles are often an afterthought during current process design and development efforts, resulting in cycles that are poorly conceived, painstakingly long, or unnecessarily wasteful. Focusing on the cleaning-system design throughout the lifecycle can yield significant cost and time savings for an organization. At the onset of a project, the equipment and piping should be reviewed for sanitary design to facilitate CIP methodology. After the design and build, cleaning cycles should be properly commissioned via testing and analysis. Often, the cleaning systems and cycles are qualified and validated as delivered, thus imposing change control barriers to conducting cleaning cycle optimization. Although the modification of cleaning cycles after validation is more complex, there is a pathway to measured and controlled improvements through mechanical design or automation development. This pathway requires balancing the benefits and desired outcomes of the optimization with the costs and available resources for design and implementation. The following is a brief look at techniques to optimize cleaning cycles throughout the equipment's lifecycle.
Equipment design

Figure 1: An example of flow-path design.

An efficient cleaning cycle begins with equipment designed to ensure successful cleaning. Tank and piping design should be reviewed for sanitary cleanability, as described in section SD-3.1 of the American Society of Mechancial Engineers Bioprocessing Equipment standard (1). This design may include minimizing deadlegs; verifying pipes are sloped toward a drain; checking for low-point drains, sanitary connections, and valves; and verifying that all product-contact surfaces are accessible to cleaning solutions. The next step in the cleanability review is to create a preliminary design of flow paths for CIP circuits. An example is shown in Figure 1. Segments of equipment and piping should be properly separated and/or combined into different cleaning circuits as part of a preliminary design. Important considerations include process and schedule requirements, potential residues, and piping design.
Process and schedule. Knowledge of the equipment's use can provide insight on process hold or transfer times. Transfer lines and tanks may need to be chained together into a single CIP circuit for quick equipment turnaround to meet these demands. Clean and dirty hold times may also affect equipment scheduling and the cleaning requirements.
Residues. Characterizing residues through cleaning studies and identifying associated product-contact surfaces aid in parameter development. Certain residues may require different cleaning solutions, concentrations, and temperatures for suitable cleaning to occur. This analysis can help organize circuits by common cleaning parameters.
Piping design. Available transfer panel connections may limit the combination of certain transfer lines and tanks. The user should account for line sizes and lengths as major pressure drops may decrease flow and turbulence within the pipe. Additional pumps and other spool pieces may be required within the system. Caution should be exercised in these cases to minimize manual configuration steps and reduce the risk of setup errors. Finally, the user should consider the availability of low-point gravity drains throughout the CIP circuit. Gravity drains remain crucial for efficient CIP cycles. 
Automation-system design
The cleaning automation design also should be reviewed for efficient cleaning characteristics. Developing cycles and sequences that complement a particular automation control system greatly reduces long-term operating costs. For instance, a fast response, direct-action, process-logic controller (PLC) may minimize rinse times and water consumption by toggling through every auxiliary path on a complex bioreactor quickly enough in parallel with the sprayballs while not extending sprayball coverage test durations. In contrast, the path transition time within a distributed-control system (DCS) depends on its programming style and may require several layers of equipment module (EM) and sub-EM commands before finally reaching the target control modules (CMs). Only after waiting for valve and state confirmations can the next step begin. Here, creating a cycle that combines multiple transitions into a single grouping will result in the shortest and most cost-efficient cycle possible. Combining cleaning actions (e.g., rinse, drain, and air blow) within phases also reduces the cycle duration. In contrast, a strategy of using more modular, individual phases may elongate the cycle.
Various time and cost-reducing methods must be balanced with skid equipment capability. For example, one may be able to take advantage of integrated PLC capabilities of equipment (e.g., vendor-provided PLC-based centrifuges). These design considerations must be identified early in the project to ensure that quality and validation procedures can be developed to address the sampling, instrumentation, and verification requirements being built into the CIP and recipient systems.
For the CIP cycle itself, the automated step sequencing, step-transition criteria, and parameter values must be well-defined and documented to optimize utility usage while providing sufficient process control. Sequence. Typically, a cleaning cycle should start with water rinses followed by detergent cleaning and postdetergent rinses. In between any rinse or detergent wash, the system should be drained completely to prevent dilution or chemical reaction with the next cycle step. An air-blow step, placed before the drain, can greatly decrease the gravity drain time and thus decrease the overall cycle time.
Transition criteria. Defining step transition criteria provides a way to control the critical cleaning-cycle parameters. For example, the chemical-wash duration, minimum temperature set point, and concentration target can all be set as requirements before the wash step transitions to the next step.
Parameter values. Laboratory-scale process residue cleaning studies can provide an excellent starting point for CIP cycle parameters. Scalable attributes, such as cleaning-agent concentration, process temperature, exposure time, and external energy, can be explored within the cleaning design space to isolate the most critical parameter(s). Combined with an evaluation of the most effective cleaning agent and identification of worst-case residues in the process, these laboratory-scale efforts can dramatically reduce the number of cycle iterations that must be performed during commissioning and allow for a focus on improving efficiency.
Commissioning
During the commissioning phase, the CIP cycle can be further optimized with hands-on development testing. Knowledge of the CIP step sequence and transition criteria are required to properly set meaningful and efficient parameters for the CIP recipes. Field verification may include monitoring drain points, viewing tank levels during recirculation, or recording pressure readings throughout the supply line.
Development testing can be aided by historical trend analysis of the test cycles. Running cycles and attempting to monitor multiple locations and parameters at the same time may be difficult with limited resources. Flow rate, pressure, temperature, conductivity, and tank-level trends, for example, can be used to optimize specific recipe parameters without having to view each instrument locally while the cycle is running. For instance, when adding chemical to a system during the recirculated wash step, the chemical must be allowed to mix evenly throughout the recirculated solution. The time required to reach the targeted steady-state conductivity can be identified by the historical trends. After comparing multiple iterations through the trends, the mixing cycle-time parameter can be set precisely based on empirical data. This method can eliminate underestimation that causes the wash recirculation to commence with nonuniform solution or overestimation that causes unnecessary cycle-time extension. These data-based decisions help maximize the efficiency of the system before validation, thus locking in cost and time gains.
Continuing optimization
After a cleaning circuit is commissioned and qualified, any changes to optimize a circuit may be difficult to implement for multiple reasons. Organizational changecontrol procedures may be burdensome, and the presented costs of a change may lead to skepticism from the control board. Whatever the restrictions or reservations, a case for cycle optimization can be made for poorly designed or inadequately commissioned cleaning circuits. More often than not, a call to optimize a cleaning circuit may lead to a long list of recommendations that can yield both time and cost savings.
When pursuing changes to a validated cleaning process, the user must understand the key cost drivers behind the optimization process. For instance, water consumption may be creating a situation in which captial investment in additional water-system capacity may be necessary. In this case, the optimization will save those additional capital costs. As another example, new products may require additional facility throughput. Reducing cycle time may be a simple way to boost overall facility throughput to achieve this goal. Often, investment of limited automation or capital resources into areas that do not directly impact the organization's key drivers will be rejected. Worse, implementing changes without understanding the cost drivers may result in beneficial improvements, but a failure to resolve the original problem. Additional time and resources will then be needed to further optimize a cleaning system that is still inefficient in the focus areas.
A thorough analysis and prioritization of potential changes can help identify an improvement path that all levels of management will endorse. Each change can be assessed with respect to its impact, ease, and necessity as well as other client constraints. Examples of items to consider are outlined below.

Table I: Optimization analysis.

• Cost reduction resulting from change. What impact will the change have on the CIP utility usage, labor costs, or maintenance costs? In the end, the ability to quantify the tangible cost savings can make or break a proposed project.
• Cycle-time reduction resulting from change. How much cycle time will be saved from parameter-value reductions or changes to procedural setup times? Cycle-time reductions should be placed in context with the overall production process to highlight the impact. This can be expressed in terms of an increase in production capacity or reduction in equipment downtime.
• Ease of change. How difficult will it be to implement the change? Take into account both the technical considerations as well as the impact on the existing validation.
• Necessity of change. How necessary is the change with regard to the cleaning cycle? Changes that improve the efficacy of the cleaning process are of primary concern.
• Other constraints. Are there any site, client, or other special constraints that may hinder or restrict the change? This may include additional change record documentation, agency approvals, available resources, or field accessibility.
• Costs of the change. What are the estimated cost implications from the change with respect to shutdown, parts and labor, and validation? These costs must be weighed against the on-going benefit of the change.

Table II: Cost-savings analysis.

Table I shows an example of the analysis and prioritization of potential optimizations. This semiquantitative analysis allows multiple projects to be compared based on predefined criteria for each category. In this case, each category is assigned equal weight, and a higher score indicates a more desirable project. Tables II and III show a more detailed analysis of the cost- and time-reduction calculations, which were translated to the ranked values in Table I using the pre-established criteria. Estimates of labor and utility costs are inputs for the comparison. Conclusion

Table III: Time-reduction analysis.

An optimal cleaning system requires effort throughout the product lifecycle. Both the mechanical and automation designs require thoughtful consideration. Optimal cleaning parameters should be explored in the laboratory design space, before scale-up and during commissioning. Once the process moves to the qualification phase, data trending and analysis should be used to establish recipe parameters. Finally, after commissioning and qualification, cycle changes and improvements should be controlled through analysis of cost, time, and resource benefits. By taking this comprehensive and holistic view, the user can truly maximize the capability and efficiency of their cleaning program.

The role of media fills in process control

New guidelines and regulations require pharmaceutical manufacturers to demonstrate that they are accurate and efficient in process control. Choosing the correct liquid media fills is an essential part of this and new culture media have been developed to help meet these stringent requirements.

Sep 1, 2006 By: Colin Booth Pharmaceutical Technology Europe

With more pharmaceutical products requiring aseptic processing to ensure end-product sterility, there is increasing emphasis being placed on procedures that demonstrate good process control. For example, stringent cleaning and disinfectant protocols, environmental monitoring, validation of equipment and process simulations (also known as media fill). The importance of these measures was highlighted in published guidance to the industry, placing even more pressure on manufacturers to show that they are getting it right when it comes to process control and meeting regulatory requirements.^1,2
Process simulations are an integral part of the validation/revalidation process and are designed to assess the likelihood of the product becoming microbiologically contaminated during the aseptic manufacturing process.
When performing a media fill, the assumption is made that all other factors that could affect the sterility of the end product — such as the sterility of containers and closures, and the efficiency of the equipment and filtration stages — are satisfactory and validated separately. The results of the media fill trial will simply demonstrate how likely it is for the contamination of units to occur throughout the 'normal' filling process.
For this reason, the trial must simulate the actual process as closely as possible, incorporating all permitted 'contaminating events'. These are events throughout the process that offer the potential for contamination and invariably involve human intervention, such as:

• changing the bulk dose container
• replenishing closures
• replenishing vials
• adjusting the speed of the filling machine
• adjusting the dose volume
• filling machine stoppages
• removing fallen vials
• staff entering or leaving the filling room/shift changes
• microbiological monitoring.

As well as stressing the importance of validating aseptic processes, the new industry guidelines have several important implications for companies performing media fill trials.
Implications of new guidelines

Figure 1 The aqueous liquid aseptic filling process.

Since the guidelines recommend that process simulations simulate the aseptic filling process as closely as possible, many companies are having to revise the design of their liquid media fills.¹ In the past, for liquid fills, the medium would be prepared and sterilized prior to being brought into the filling room and attached to the filling machine using an aseptic connection. However, in the aseptic process, the liquid pharmaceutical product would be placed in a non-sterile bulk container outside the filling room and then filter sterilized, through a filter train, into a sterile bulk container within the filling room. To simulate this process exactly, the medium would have to go through the same filtration step (Figure 1). This raises several concerns, for example

• Dehydrated culture media are usually supplied in a non-sterile form and carry a high bioburden (> 10⁴ cfu/g), preventing them from being taken directly into the support clean area where the bulk non-sterile vessel would be.
• For liquid fills, many holding vessels upstream of filtration do not have the capability to heat culture media to an adequate temperature to dissolve the powder into a solution. Even for those that have this ability, the time and energy used in heating and cooling is considerable and costly.
• Mycoplasmas present in the non-sterile dehydrated medium may be able to pass through some filters.
• Broths traditionally used for media fills do not have good filterability characteristics and could block the sterilizing filters before the end of the run. This would invalidate the process simulation and the trial would have to be repeated. Not only is this a waste of time and resources, but it increases the downtime of the filling area with obvious financial implications for the manufacturer.

The new guidelines also recommend an increase in the number of units required to be filled in a process simulation. Run sizes of between 5000 and 10000 units are now recommended (or, if a production run size is less that 5000, the number of media filled units should at least equal the maximum batch size) to demonstrate that aseptic processing is being achieved (< 0.1% contamination with a 95% confidence limit).¹
Moreover, the requirement to include all contaminating events, including worst case conditions, may often take the run size to more than 10000 media filled units. This increase in the number of filled units required will, in turn, increase the volume of medium required. If the medium has to be filter sterilized in the simulation process, the volume of medium used (in addition to its filterability) will also have an affect on the life of the filter.
All of these issues must be taken into account when selecting the growth medium to be used in a process simulation.
Three consecutive successful process simulations are required every 6 months for every filling process performed by a pharmaceutical company. By ensuring that the media fill runs smoothly (without delays caused by heating large quantities of medium or blocked filters), the length of time that the production line is out of action can be kept to an absolute minimum.
Choosing the right medium
The most commonly used medium is tryptone soya broth (TSB), also referred to as soybean casein digest medium.¹ This is a good, general purpose medium that will support the growth of a wide variety of micro-organisms. TSB has been used by the pharmaceutical industry for many years in process simulations, but with the evolution of trial design to accommodate updated regulatory requirements, many standard TSB products are not able to meet the most recent demands of the industry.
Newer products are now available, however, that address these demands, ensuring a successful trial whilst satisfying the regulatory bodies. The ideal product is an irradiated, cold-filterable TSB with known filterability, for several reasons

• Irradiation of the medium, at a level ≥ 25 kGy, ensures that the dehydrated medium is suitable for use in pharmaceutical clean areas. Irradiation also eliminates the threat of contamination by mycoplasmas.
• It is now possible to obtain cold-filterable TSB that will dissolve in water without heating. Unlike standard TSB products, this medium is highly filterable, reducing the risk of blocked filters during process simulation. Furthermore, since heating is not required to make the medium dissolve or filter, it is more efficient and cost effective and is suitable for use in vessels that do not have heating capability.
• Pharmaceutical companies are now able to obtain irradiated, cold-filterable TSB with a known filterability. The volume of medium able to pass through a filter of a certain pore sizing before the filter blocks, is known as the V_max or V_cap. For media with a known V_max, pharmaceutical companies can calculate whether the filter will cope with the total volume of medium required to complete the trial. This will reduce the number of invalid trials because of filter blockages.

Another regulatory concern that affects the choice and source of the culture media is the threat of prion contamination. Prions are infectious agents responsible for a range of neuro-degenerative diseases known as transmissible spongiform encephalopathies (TSEs).
It is known that the human form of the disease, new variant Creutzfeldt-Jakob Disease (nvCJD) can be transmitted from prion contaminated animal material.³ There is currently no vaccination or cure for prion diseases and contamination of a parenteral or infusion pharmaceutical product could prove fatal.⁴
Many culture media, including TSB, contain components of animal origin — frequently bovine. Prions require specific heat or chemical treatment to be inactivated. Furthermore, there is no in situ method available for the detection of these particles.
It is vitally important that the culture media manufacturer can provide the necessary certifications and documentation to confirm that materials of animal origin are sourced from 'BSE-free' countries to meet regulatory requirements. An alternative approach would be to use a medium derived purely from vegetable materials.
Meat-free alternatives
In response to the issue surrounding materials of animal origin, some culture media manufacturers have developed meat-free media in which components derived from animals are replaced with vegetable-based materials. However, for this media to be a viable alternative for the pharmaceutical industry, they must be able to demonstrate performance characteristics at least equivalent to those of traditional meat-based media.
Conclusion
Although new guidelines and regulations are placing greater demands on pharmaceutical manufacturers to demonstrate process control, the development of culture media is keeping pace to help meet these stringent requirements.
Products such as irradiated, cold-filterable TSB and alternative meat-free media can help pharmaceutical manufacturers to meet these challenges.

References
1. FDA Guidance for Industry — Sterile Drug Products Produced by Aseptic Processing — current Good Manufacturing Practices, 2004 (US Food and Drug Administration 5600 Fishers Lane, Rockville MD 20857-0001, USA).
2. European Commission Guide to Good Manufacturing Practice, Annex 1, Manufacture of Sterile Medicinal Products, 2004 (EMEA, 7 Westferry Circus, Canary Wharf, London, UK).
3. J. Collinge, et al., Nature 383(6602), 685–690 (1996).

Media Fill Trials as Process Simulations in Pharmaceutical and Biotech Manufacturing

Key Characteristics a MFT is an aseptic production run using sterile culture media designed to assess contamination risk of that process culture media specifically designed for media fill trials are available

Introduction

Sterilization is an absolute term, and microbiologists strive to achieve this state in much of the preparation work that they do through various processes usually involving heat, toxic gases or irradiation. Where the absolute condition cannot be achieved without product degradation, qualified working definitions apply; the regulation of pharmaceutical manufacture allows for the absence of viable microorganisms in aseptic filling processes.

Clearly, the challenge is to design such processes to eliminate the risk of contamination. Media fill trials as process simulations are not new, but the emphasis is evolving away from just the trial result to include process design and risk analysis. All regulatory frameworks now advocate risk based management and an integrated quality system approach to drug manufacture.

By adopting a more holistic approach to aseptic processing, rather than strict adherence to guidance documentation, factors such as environmental awareness, and the role of staff training serve to complete a picture that will contribute to control and ultimately eliminate the risk of product and patient compromise.

Process simulation

Supplier reference for these items: Media for MFT

Process simulation studies should be designed to emulate the routine production process as closely as possible, including formulation, filtration and filling stages. Processes will vary in relation to the type of product to be filled, e.g. liquid or solid dosage forms, and each process simulation is a unique event whereby extrapolation of outcomes cannot be directly linked to actual process contamination rates. The study will be performed using microbiological growth media in place of active pharmaceutical ingredients (API). This is a 'worst case' senario as most pharmaceutical products normally would not support microbiological growth. The selection of the medium should be based on its ability to integrate into the process at the earliest formulation stage and therefore have the capacity to be introduced to the filling process by filtration. Also the growth promotion characteristics should allow recovery of the typical flora recovered from environmental monitoring programs. The microbiological culture media itself can potentially be a source of contamination so to avoid a culture media related positive fill test, the media is irradiated and can be presented either in the dehydated format or as a ready to use broth. Modern culture media, designed for media fill trials, possess certain attributes that facilitate process simulations; they will be irradiated making them suitable for introduction into compounding areas, will dissolve in cold water and have known filtration performance as standard broth can be slow to filter or block the filter. Also, those who wish to use an animal-free product can now obtain a vegetable alternative. Following formulation, filtration and filling the closed vessels are incubated and inspected for contamination.

Future concepts

It is important to remember that, as described in ISO 13408-1, the process simulation test is only a snapshot of the process design and cannot ensure that product fills using the same process will share the same microbiological quality.

In 2005, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) issued guidance dealing with risk management plans for the aseptic processing of pharmaceutical products. In 2007, an annex to ICH Q8 Pharmaceutical Development, the principle of quality by design (QbD) is described. ICH Q9 Quality Risk Management is defined as "a systematic process for assessment, control, communication and review across the product lifecycle". This takes into consideration the fact that understanding a process must take into account system risks (facility, people, organization), process risks (operations), and product risk (safety, efficacy).

Consistent with the objectives and approach of risk management is the adoption of technological advances. Understandably conservative in applying novel microbiological techniques, efforts are developing to address the “regulatory uncertainty” surrounding non traditional approaches. The pharmaceutical industry is now encouraged under the FDA PAT (process analytical technologies) initiative to embrace validated and qualified microbiological advances.

This holistic risk management approach to aseptic processing will facilitate continual improvement and drive the confidence of sterility beyond the 95% boundar

Mobile, Roofless Clean Room Proposed by Orion Engineers

The first space-worthy Orion Multi-Purpose Crew Vehicle (MPCV) will soon start to be assembled at the NASA Kennedy Space Center (KSC), in Florida, the former home of the space shuttle fleet. Engineers say that a mobile, roofless clean room could be built around the spacecraft.

For many years, scientists believed that a clean room-like environment could only be achieved by controlling the conditions inside a specially-designed, well-isolated chamber very rigorously. Now, they are beginning to figure out that this may not be the case at all times.

Currently, NASA is testing a design where the clean room is installed around the spacecraft being built. This is a significant departure from regular standards, where the vehicles are assembled inside aseptic conditions, Science Daily reports.

The concept was developed by Austin, Texas-based aerospace company Astrotech Corporation. Engineers here came up with the idea to build an installation that would ensure no dust settles on the spacecraft's surface.

They say that installing two, 10-foot (3-meter) high walls of filter-equipped fans on either side of the capsule could create an even airflow, and enough air motion to prevent any particles from settling on the MPCV's components.

The other two walls of the clean room would be made up of clear materials, and the ceiling would be non-existent. Astrotech experts explain the lack of a roof by the necessity to access the large cranes already installed inside the KSC Vehicle Assembly Building (VAB).

These cranes will be used to hoist the completed Orion atop the Space Launch System (SLS) rocket NASA is developing for its new spacecraft. The delivery system's maiden flight is scheduled for no earlier than 2017.

“The guys over in the Operations and Checkout Building are using this and that's what gave us the idea. It's pretty innovative, so we'll see if it works,” NASA Ground Systems Development and Operations Program engineer, Doug Lenhardt, says.

“The results have been encouraging. We don't have the full story yet, but it's been encouraging,” he concludes.