tag:blogger.com,1999:blog-21508660020298735482024-03-13T16:48:24.148-07:00Pharmaceutical infoNiazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.comBlogger1368125tag:blogger.com,1999:blog-2150866002029873548.post-27272439571265238642016-11-05T14:52:00.000-07:002016-11-05T14:52:22.754-07:00Barrier Isolators and Microenvironments for Cleanroom Applications<div style="box-sizing: border-box;">
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Source: Absolute Control Systems</div>
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<span style="box-sizing: border-box; font-weight: 700;">Introduction </span><br style="box-sizing: border-box;" />This presentation provides relevant information regarding the advantages of using Barrier Isolators and Microenvironments in cleanrooms, primarily in semiconductor and pharmaceutical applications. This narrative is a discussion regarding the need for the technology, followed by general equipment features common to both pharmaceutical and semiconductor industries. The Cleanrooms East presentation includes numerous viewgraphs covering this topic followed by examples of enclosure systems which were successfully integrated into clean manufacturing facilities.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Definitions</span><br style="box-sizing: border-box;" />First, a few unofficial definitions of terms used throughout this presentation. The term Process refers to the activity that must be performed. The equipment being discussed here is used to contain or isolate the process and process equipment for the purpose of protecting the process from the environment, protecting the environment from the process, or both.</div>
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A Barrier system is an engineered device which provides a simple, single method of separating a process from the surrounding environment. No environmental parameters are typically controlled; the operator can see the process, but can not touch it without defeating the device. Interlocks may be provided to prevent or stop a process within the barrier if a perimeter door is opened. The simple barrier assures that nothing impedes the flow of air from the cleanroom ceiling downward to the process.</div>
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A microenvironment is an engineered enclosure system used to maintain low-particulate environment around a semiconductor production-related process. Temperature, overpressure, relative humidity, air flow and make up air may be controlled. Interfaces are carefully designed to maintain the conditions inside the enclosure. The process may represent a hazard to operator and facility.</div>
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A Barrier Isolator is an engineered enclosure system used to maintain an aseptic / sterile, low- particulate environment around a pharmaceutical production-related process. Temperature, overpressure, relative humidity, air flow, and make up air balance may be manipulated to enhance aseptic conditioning efforts. Interfaces (a b or rtp) are carefully designed to maintain the conditions inside the enclosure.</div>
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A Containment Isolator is used to contain Potent, Hazardous, or Toxic (PHT) chemical compounds or liquids. Complexity of these systems varies depending on the level of hazard that must be contained. The enclosure is maintained at a negative pressure with respect to the surrounding room, in an effort to keep PHT compounds within the isolator system should a leak occur. In pharmaceutical production, powders, liquids, and slurries are routinely transferred from one container or vessel to another. Containment isolators have found utility as secondary containment between two vessels during make- break operations. Many finished pharmaceutical products retain the PHT properties after sterilization, and must remain pure for human consumption. Once sterile, the handling and packaging of these materials becomes a complex problem due to the requirement for isolation (aseptic / sterile) and containment (PHT) simultaneously.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Advantages</span><br style="box-sizing: border-box;" />Why consider barrier isolation technology in the cleanroom? The answer is that this technology is required to achieve full potential of modern process tools. Historically, hoods or clean benches have been used to provide localized "special" conditions within a clean manufacturing facility. Because hoods and clean benches work on the principal of dilution and filtration (respectively) combined with directional air flow, a large volume of air must be moved, which translates to energy cost. They are "single ended" devices, meaning they pull or push air, but not both. They require the facility to provide particle collection or make up air. The facility must be properly designed for the correct rate of air changes and volume of make up air, and system balance may be subject to transient upset due to movement of people, equipment, and product through the ballroom.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Small scale cleanroom</span><br style="box-sizing: border-box;" />Raised floor cleanrooms use the principal of flowing (purging) filtered air over the process (and people), and collecting the return air, which helps remove particles from the suite. A properly designed enclosure system accomplishes the same thing, on a smaller scale. More air changes may be accomplished for a given energy cost by reducing the size of the zone of concern.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Cleanable Zone of Concern</span><br style="box-sizing: border-box;" />Eventually, any open system collects debris. Sources include people, garments, process materials, process tools, and debris from system upsets. A closed system has the potential for higher levels of isolation and contamination control by removing non-essentials from the zone of concern and reducing that zone to the smallest area possible. Properly designed, a closed system can be cleaned better, and kept clean longer.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Plan ahead</span><br style="box-sizing: border-box;" />Murphy's Law teaches that if anything can go wrong, it will, and at the worst possible time. A transient process upset, spill, or accident may spread contamination in the facility. My experience has been that for many clients who are currently using this technology, there is an first generation system which now resides in the "bone yard", because it can no longer be used. The overwhelming reason for this has been cross contamination and/or redeposition issues; the equipment became inadvertently contaminated by well intentioned individuals and circumstances. Proper design and forethought is of paramount importance. The closed system affords superior operator protection over open systems where significant hazard to the operator exists when properly designed.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Operator Protection</span><br style="box-sizing: border-box;" />The topic of protection brings up two important points. If there is a hazard to the operator, simply removing the operator may solve the biggest part of the problem. Consider also that people can be hazardous to many processes, and removing them is again desirable. A common way to accomplish both is to contain the operator in a gown or air suit, and some operations cannot be performed without operator containment. The reason is usually that the equipment which is integral to the process is not designed for isolation. In most cases, the cost of gowning and airsuits is a major cost of operation, and they increase operator discomfort. It is desirable then to reduce the level of gowning from both a cost and operator comfort standpoint. Barrier isolation technology affords the opportunity to completely remove the operator from the zone of concern.</div>
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<span style="box-sizing: border-box; font-weight: 700;">People are Dirty</span><br style="box-sizing: border-box;" />Because people cannot be sterilized, and don't stay really clean for long, they carry undesirable particulate and biological contamination in and out of the clean area. The isolation system, on the other hand, can withstand vigorous wash down, sanitizing, or other operations due to the hard materials of construction. Unique atmospheres may be introduced in high concentrations, and then removed to extremely low residual levels. Temperatures, pressures, humidity levels that humans and pathogens cannot withstand may be manipulated within the enclosure. The materials of construction and methods of finishing result in a non shedding, non porous, non reactive wetted surfaces in the zone of concern.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Superior Environment Control</span><br style="box-sizing: border-box;" />Precise control over environmental parameters is achievable within an enclosed system, such as precision temperature control. One example for the need for precise temperature control is precision metrology, where the Absolute Control Systems temperature is of less importance, but the established temperature must be rigidly maintained (+/- 0.1 degree, for example) regardless of external influences. Other environmental parameters may be controlled and manipulated. Class 1 particulate levels are routinely achieved using ULPA grade filters. Low oxygen or moisture atmospheres measuring less than 1 part per million (<1 a="" allow="" anaerobic="" are="" atmospheres="" by="" compartments="" different="" exist="" for="" handling="" hygroscopic="" if="" materials.="" multiple="" of="" on="" or="" ppm="" produced="" pyrophoric="" range="" reactive="" required="" scale="" sections="" small="" system="" the="" to="" with=""></1></div>
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<span style="box-sizing: border-box; font-weight: 700;">What to Expect</span><br style="box-sizing: border-box;" />Without providing a detailed cost analysis, your can reason that by reducing the zone of concern to the smallest reasonable area, you should anticipate an overall reduction in operating costs, right? Well, maybe. Most production equipment is not yet designed for isolation, and such equipment is not an "off the shelf" procurement. Plan on becoming a "quasi-expert" on this technology to implement it to its fullest potential. Clearly, an enclosed system must be a fully engineered system to properly address all aspects of the critical service which is required of it.</div>
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Increased product yield and quality is the ultimate goal of most manufacturers. Increased yield pays the bills. The use of this technology is a capital expenditure, so there is a cost-benefit argument. Other studies have shown that initial costs are higher per installation than conventional ball room suites, but the cost of operation is somewhat lower. It is clear that this technology is not driven by a need to reduce costs, rather by the need for increased performance.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Intangibles</span><br style="box-sizing: border-box;" />There are other benefits. Installing a great looking piece of equipment, that enhances the capabilities of your facility, can potentially bring additional work or recognition to your site and yourself. A properly designed environmental enclosure or workstation will be smoothly integrated into the facility.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Competition and Regulation</span><br style="box-sizing: border-box;" />Eventually your competition will implement this technology, and you'll have to react to keep up. After all, competition drives the marketplace and regulation constantly raises the bar.</div>
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Current FDA regulations required extensive documentation, testing and validation activities take place prior to use of pharmaceutical production equipment. The approval is site specific, so if the process is moved to another location, the validation and certification activities must be performed again. The future holds the possibility that fully enclosed and integrated systems may eventually be approved for use prior to being shipped to a remote site.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Safety is Important</span><br style="box-sizing: border-box;" />As concern for personal injury litigation is at an all time high, there a responsibility to provide "best available" technology with regard to worker safety. Regardless of whether the hazard is an airborne powder in a pharmaceutical facility or a class 4 invisible laser used in a wafer fab, the fact is that worker safety concerns exist shoulder to shoulder with production concerns in many cleanroom applications.</div>
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<span style="box-sizing: border-box; font-weight: 700;">Do I need One? </span><br style="box-sizing: border-box;" />The use of Absolute isolation or containment is based on need. To determine when to employ this technology, I offer a simple rating system. If you apply a one to five scale, with five being the most acute hazard or sensitive process, then these systems are intended for the highest level of concern, ratings four and five. Level One concerns are handled in open areas with operators wearing the minimal level of personal protection, perhaps with a simple barrier method. Level Two and Three concerns typically are handled in controlled areas with operators wearing the appropriate level of personal garb, and utilizing clean benches, hoods and biosafety cabinets to maintain the facility.</div>
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Product properties that may indicate the need for isolation / containment.</div>
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<li style="box-sizing: border-box;">Flammability</li>
<li style="box-sizing: border-box;">Nuisance dust</li>
<li style="box-sizing: border-box;">Explosive dust hazard</li>
<li style="box-sizing: border-box;">Corrosive properties</li>
<li style="box-sizing: border-box;">Irritants</li>
<li style="box-sizing: border-box;">Allergens</li>
<li style="box-sizing: border-box;">Sensitizing agents</li>
<li style="box-sizing: border-box;">Toxins</li>
<li style="box-sizing: border-box;">Carcinogens</li>
<li style="box-sizing: border-box;">Mutagens</li>
<li style="box-sizing: border-box;">Biohazards</li>
<li style="box-sizing: border-box;">Low bioburden</li>
<li style="box-sizing: border-box;">Germ free</li>
<li style="box-sizing: border-box;">Live virus</li>
<li style="box-sizing: border-box;">Visual hazard - laser</li>
<li style="box-sizing: border-box;">Physical hazard - moving components</li>
<li style="box-sizing: border-box;">Volatile Organic Compounds (VOC) - Emissive agents</li>
<li style="box-sizing: border-box;">Sterilants</li>
<li style="box-sizing: border-box;">Extreme Absolute environment - vacuum, pressure, temperature, moisture</li>
<li style="box-sizing: border-box;">ULPA class environment</li>
<li style="box-sizing: border-box;">Anaerobic</li>
<li style="box-sizing: border-box;">Unique inert gas backgrounds</li>
<li style="box-sizing: border-box;">Cross contamination between products</li>
<li style="box-sizing: border-box;">Precision cleaning - microcontamination</li>
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<span style="box-sizing: border-box; font-weight: 700;">Summary</span><br style="box-sizing: border-box;" />In summary, Absolute Control Systems containment and isolation is a maturing technology that offers advantages to operators of clean manufacturing facilities. A properly designed and constructed process isolation system offers the potential for tighter control of multiple environmental parameters surrounding a sensitive process than can be achieved in an open cleanroom.</div>
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Like any emerging technology, there is no one set of standards. The project professional who elects to utilize this technology in his or her facility must be aware of the potential pitfalls as well as the merits. Bring in experts early in the development process. Develop a detailed performance-based specification and review it with your operations and maintenance personnel. Select a competent design / build vendor with a proven track record. Thorough planning in the early stages will assure success. Good luck in your project.</div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-86420715142390495662016-11-05T14:47:00.003-07:002016-11-05T14:47:51.038-07:00Sterility Testing: Beware of the Pitfalls<div style="background-color: white; box-sizing: border-box; color: #333333; font-family: Georgia, serif; font-size: 14px;">
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<i style="box-sizing: border-box;">By Martin Spalding, Jr., Northview Laboratories</i></div>
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<a href="https://www.blogger.com/null" name="top" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Contents</span></a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#int" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Introduction</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#the" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">The Fundamental Limitation</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#pro" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Protecting the Integrity of the Process</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#cau" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Causes of True Positives</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#lim" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Limitations of Testing Defined</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#are" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Are Isolators the Answer?</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#dea" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">Dealing with Sterility Test Positives</a><br />
<a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#ref" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;">References</a></div>
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<a href="https://www.blogger.com/null" name="int" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Introduction</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a></div>
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"We have a failure on your sterility test."</div>
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Every manufacturer dreads hearing those words. Your first reaction may be to say, "Lab-induced contamination!" And you could be right. But that doesn't mean your testing lab was negligent. More likely you're the victim of the inherent limitations of traditional sterility testing. Statistically, the test itself has a failure rate higher than the process it's designed to monitor.</div>
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Sterility testing is widely used in both the medical device and pharmaceutical industries. As a USP test, it is the official procedure for testing the sterility of pharmaceutical products. It is also used on terminally sterilized medical devices, both as a lot release test and for the dose audit phase of sterilization validations.</div>
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Despite its importance and its widespread use, most people are not aware of the limitations of the sterility test. The following discussion pertains to conventional sterility testing using direct transfer techniques and not to sterility testing performed in an isolator. Some points apply more to medical devices than pharmaceuticals, as devices are generally more difficult to test.</div>
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<a href="https://www.blogger.com/null" name="the" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">The Fundamental Limitation</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
The fundamental limitation of sterility testing is that the sterility assurance level (SAL) for the process of conventional sterility testing is lower than that for the sterilization processes that it is used to monitor. Unfortunately, there's no escaping the fact that during the test, microorganisms are in close proximity to both the test samples and the open container of culture medium to which the samples must be transferred.</div>
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Why are these microorganisms so close to the testing process? Because sterility tests must be performed by people, and people are a prolific source of microorganisms. Humans present a huge introduction of bacteria into the cleanroom, with a total normal flora of >10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">14</span></small> living bacteria cells, 10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">12</span></small> of these residing on the skin and 10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">10</span></small> in the mouth.<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">1</span></small> Besides the technicians, test sample packaging, media containers, or testing supplies can be sources of contamination. Through stringent technique, the impact of these and other sources of microorganisms can be minimized, but not eliminated.</div>
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<a href="https://www.blogger.com/null" name="pro" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Protecting the Integrity of the Process</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
Laboratories take extensive precautions to protect the integrity of the sterility testing process. Test samples are removed from the cartons in which they were processed in a nonsterile area, since cardboard harbors many microorganisms and should not enter a sterility test cleanroom. Then, before the samples enter the cleanroom, their exteriors must be disinfected. Note that disinfection is <i style="box-sizing: border-box;">not</i> the same as sterilization. Some microorganisms may remain on the surface of a sample package and end up in the HEPA-filtered hood during the sterility test.</div>
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<small style="box-sizing: border-box; font-size: 12.8px;"><i style="box-sizing: border-box;"><span style="box-sizing: border-box; font-weight: 700;">Swipe testing is a first-line defense against microbial contamination, but swiping only tells you after the fact if your process is contaminated.</span></i></small></center>
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Culture media for sterility testing must be prepared and steam sterilized in a validated autoclave cycle. It must be subjected to USP growth promotion testing, so up to several days may elapse from the time the media is sterilized until its use in testing. During this time, the exterior of the media containers may pick up microbial contamination, even if stored in a cleanroom. So, like the test samples, the media containers must be disinfected prior to being transferred into a laminar flow hood for sterility testing. Also, the work surface of the hood is disinfected before each sterility test, and the entire cleanroom each testing day.</div>
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Sterility test technicians must be fully gowned to contain the microorganisms on their skin and clothing and to protect test samples. Typically, technicians wear a hair cover, hood, face mask, goggles, coverall, shoe covers, and gloves—all sterile, of course. Technicians must be thoroughly trained in proper gowning technique, and in aseptic technique, which is absolutely essential to the sterility testing process.</div>
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<a href="https://www.blogger.com/null" name="cau" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Causes of True Positives</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
Because of all of these precautions, the laboratory generally has a high degree of confidence in the results of the sterility test. True positives will occur due to a variety of causes—an inadequate sterilization cycle, inadequate delivery of the sterilization process to the sample, underestimation of product bioburden, bioburden spikes, resistant organisms on the product, or compromised packaging. These possible causes must be considered whenever a positive occurs.</div>
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<a href="https://www.blogger.com/null" name="lim" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Limitations of Testing Defined</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
Despite stringent operating procedures, good cleanroom practice, and the use of sound aseptic technique, occasional false positives will occur. A microorganism that was not on the test sample will get into a media container used in a sterility test. Experienced microbiologists acknowledge the technical limitations of sterility testing. USP 23 officially recognizes the limitations of sterility testing in two ways. First, chapter <71>, Sterility Tests, permits retesting if an investigation indicates that inadequate or faulty aseptic technique was used in the test. Second, chapter <1211>, Sterilization and Sterility Assurance, describes a sterility assurance level on the order of 10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">-3</span></small> for the sterility testing process. <i style="box-sizing: border-box;">This means that for every 1000 samples tested, one false positive will occur.</i></1211></71></div>
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This 10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">-3</span></small> SAL, a common reference in the pharmaceutical industry, is based on experience with the sterility testing of pharmaceutical products, typically liquid products in vials. The actual sterility assurance level for the testing of a specific product can vary significantly, depending on the difficulty of the testing procedure. Many medical devices are particularly difficult to sterility test due to the extensive sample manipulation and large media volumes required. So the sterility assurance level for testing a given medical device may be less than the 10<small style="box-sizing: border-box; font-size: 12.8px;"><span style="box-sizing: border-box; font-size: 9.6px; line-height: 0; position: relative; top: -0.5em; vertical-align: baseline;">-3</span></small> level typical for pharmaceutical products.</div>
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<a href="https://www.blogger.com/null" name="are" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Are Isolators the Answer?</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
False positives occasionally occur in even the most diligent conventional sterility testing operations. So major pharmaceutical companies are investing millions of dollars in sterility testing isolators. Isolators are completely enclosed HEPA-filtered chambers that typically are interfaced with a vapor phase hydrogen peroxide (VHP) sterilizer and/or a steam sterilizer. Sterility testing is performed from outside the unit through glove ports or halfsuits. The testing process is totally isolated from people.</div>
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Sterility testing isolators are expensive to install and validate. At the low end, a small isolator with a VHP sterilizer costs at least $250,000. Some pharmaceutical companies have invested over $4 million in more elaborate isolator set-ups.</div>
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Unfortunately, it would be difficult and expensive to test most medical devices in a sterility test isolator. A major problem is that Tyvek is permeable to VHP, so elaborate precautions must be taken to avoid undermining the integrity of the sterility test. Also, the size of many medical devices, the number of samples tested, and the volume of test supplies (including one or two media containers per test sample) would dictate the use of a relatively large isolator. To switch to a sterility test process using an isolator and a VHP cycle, manufacturers would have to validate the process for each product. The time required to perform the test would increase greatly in comparison to conventional sterility testing. This means that costs for isolator sterility tests of medical devices could be 3 to 10 times greater than for conventional testing.</div>
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Would the increased costs be justifiable for the average manufacturer? Consider the options available when the inevitable sterility test failure occurs. Unlike the aseptically filled pharmaceutical product, which must be discarded if positives are confirmed, most terminally sterilized medical devices can be reprocessed. An occasional resterilization would be far less expensive than routine testing in an isolator.</div>
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<a href="https://www.blogger.com/null" name="dea" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">Dealing with Sterility Test Positives</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a><br />
What's the bottom line? If you rely on conventional sterility testing, you will eventually have to deal with sterility test positives. Some positives will indicate the presence of microorganisms on the product itself. Others may be due to a contaminant introduced during the sterility testing process.</div>
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So be prepared. Write procedures detailing your plan to handle positives when they occur. Give yourself some options in addition to resterilization. In the event of a sterility test positive, the lab may have evidence that would justify invalidation of the test. Your SOPs should state what action to take if the laboratory interprets a sterility test positive as lab-induced. It's also a good idea to evaluate the effect of a second sterilization cycle on your product. Often, this is the fastest way to get beyond the problem. Many manufacturers address the issue of resterilization during their sterilization validation, packaging, and functionality testing.</div>
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Isolators have become a valuable technology for some pharmaceutical product manufacturing and sterility testing. For other products, particularly medical devices, conventional sterility testing continues to be an essential tool for validating the effectiveness of the sterilization process. But microorganisms can behave in unpredictable ways. So if you rely on sterility testing, be aware of its limitations!</div>
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<a href="https://www.blogger.com/null" name="ref" style="background-color: transparent; box-sizing: border-box; color: #326891;" target="_blank"><span style="box-sizing: border-box; font-weight: 700;">References</span></a> <a href="http://www.pharmaceuticalonline.com/doc/sterility-testing-beware-of-the-pitfalls-0001#top" style="background-color: transparent; box-sizing: border-box; color: #326891; text-decoration: none;"><small style="box-sizing: border-box; font-size: 12.8px;">(Back to Top)</small></a></div>
<ol style="box-sizing: border-box;">
<li style="box-sizing: border-box;">William Hyde, <i style="box-sizing: border-box;">PDA Journal of Science and Technology,</i> "Origin of Bacteria in the Clean Room and Their Growth Requirements", July/August 1998, Volume 52, Number 4, p. 154.</li>
<li style="box-sizing: border-box;"><i style="box-sizing: border-box;">USP 23,</i> <1211> Sterilization and Sterility Assurance, p. 1980.</1211></li>
<li style="box-sizing: border-box;">Hank Rahe, <i style="box-sizing: border-box;">American Pharmaceutical Review,</i> "Implementing a Cost Effective Sterility Testing Isolator Project, Volume 1, Issue 1, 1998, pp. 34–41.</li>
</ol>
</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com2tag:blogger.com,1999:blog-2150866002029873548.post-71535911632381083132016-11-05T14:43:00.001-07:002016-11-05T14:43:35.343-07:00Hydroxytyrosol augments the redox status of high fat diet-fed rats<h2 class="secHeading" id="authorabs00051" style="background-color: white; border: 0px; clear: both; color: #5c5c5c; font-family: Arial, Helvetica, "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", STIXGeneral, "Cambria Math", "Arial Unicode MS", sans-serif; font-size: 18px; font-weight: 100; line-height: inherit; margin: 20px 0px 6px; padding: 0px; vertical-align: baseline;">
Abstract</h2>
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Hydroxytyrosol (HT) is being investigated for its manifold biological activities. In this study, we assessed whether HT could lessen the metabolic and redox imbalance caused by high-fat diet, in a rat model. Male Wistar rats were divided into four groups (n = 4 each), homogeneous for age and weight. Group 1: control diet; Group 2: control diet + 20 μg HT/d by oral gavage; Group 3: high fat, high carbohydrate diet; Group 4: high fat, high carbohydrate diet +20 μg HT/d by oral gavage. The experiment lasted four weeks. The addition of HT to the high fat diet did not slow down weight gain as compared to the unsupplemented diet. No significant differences in glycemia were observed among the four experimental groups. Ascorbic acid plasma concentrations at the end of the experimental period were non-significantly lower in high fat diet rats than in control animals. Plasma, but not erythrocytes hydroperoxide concentrations were significantly lower in group 4 animals as compared with the other ones. The high-fat diet induced protein carbonyl formation. Even though supplementation with HT lowered carbonyls’ concentrations, the effect did not reach statistical significance. Conversely, the action of HT became significant when plasma MDA was measured.HT also increased serum antioxidant capacity, assessed as ORAC of total serum and as conjugated diene formation of copper-oxidized isolated LDL/HDL.</div>
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Public heath bodies should actively discourage the adoption of obesogenic high-fat diets, but HT as supplement modulates some of their harmful effects.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-78568773765749842392016-11-05T14:40:00.002-07:002016-11-05T14:40:26.365-07:00Role of long-chain omega-3 fatty acids in psychiatric practice <h2 class="subTitle paddingT7 paddingB10" style="color: #5c5c5c; font-family: Arial, "URW Gothic L", Helvetica, Tahoma, sans-serif; font-size: 1.2em; font-weight: 100; line-height: 1.5em; margin: 0px; padding-bottom: 10px; padding-top: 7px;">
Abstract</h2>
<div align="justify" class="marginB3" id="recordAbs" style="color: #2e2e2e; font-family: Arial, "URW Gothic L", Helvetica, Tahoma, sans-serif; font-size: 13.3333px; padding-bottom: 1px; text-align: justify;">
Nutrition plays a minor role in psychiatric practice which is currently dominated by a pharmacological treatment algorithm. An accumulating body of evidence has implicated deficits in the dietary essential long-chain omega-3 (LC. n-3) fatty acids, eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology of several major psychiatric disorders. LC. n-3 fatty acids have an established long-term safety record in the general population, and existing evidence suggests that increasing LC. n-3 fatty acid status may reduce the risk for cardiovascular disease morbidity and mortality. LC. n-3 fatty acid supplementation has been shown to augment the therapeutic efficacy of antidepressant, mood-stabilizer, and second generation antipsychotic medications, and may additionally mitigate adverse cardiometabolic side-effects. Preliminary evidence also suggests that LC. n-3 fatty acid supplementation may be efficacious as monotherapy for primary and early secondary prevention and for perinatal symptoms. The overall cost-benefit ratio endorses the incorporation of LC. n-3 fatty acids into psychiatric treatment algorithms. The recent availability of laboratory facilities that specialize in determining blood LC. n-3 fatty acid status and emerging evidence-based consensus guidelines regarding safe and efficacious LC. n-3 fatty acid dose ranges provide the infrastructure necessary for implementation. This article outlines the rationale for incorporating LC. n-3 fatty acid treatment into psychiatric practice. © 2013 Elsevier B.V.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-45094640046443448892016-11-05T14:38:00.003-07:002016-11-05T14:38:36.448-07:00Opioid Poisonings Rise Sharply Among Toddlers and Teenagers <header class="story-header" id="story-header" style="background-color: white; margin-left: 0px; margin-right: 0px; position: relative;"><div class="story-meta " id="story-meta" style="margin-bottom: 20px;">
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The number of children being hospitalized because of prescription opioid poisoning has risen sharply since 1997, especially among toddlers and older teenagers, researchers from the Yale School of Medicine reported.</div>
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The <a href="http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamapediatrics.2016.2154" style="color: #326891;">study, published Monday in</a><a href="http://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamapediatrics.2016.2154" style="color: #326891;"> JAMA Pediatrics</a>, analyzed data from the <a href="https://www.hcup-us.ahrq.gov/kidoverview.jsp" style="color: #326891;">Kids’ Inpatient Database</a>, a national database of pediatric hospitalizations. Looking at data gathered every three years from 1997 through 2012, they identified 13,052 instances in which children and teenagers ages 1 to 19 had been hospitalized for prescription opioid poisonings; 176 of them had died.</div>
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Among children ages 1 to 4, hospitalizations for opioid poisoning increased by 205 percent. For 15- to 19-year-olds, hospitalizations rose by 161 percent.</div>
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Children ages 1 to 4 were hospitalized primarily for accidentally ingesting opioids, while the majority of teenagers over 15 took the drugs with the intent to commit suicide, said Julie R. Gaither, the study’s lead author and an epidemiologist and postdoctoral fellow at Yale. She said other teenagers had probably overdosed when taking the drugs for recreational purposes. She attributed the increase in poisonings among toddlers to parents or other adults in the household leaving pills within easy reach.</div>
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Dr. Gaither said poisonings attributed to prescription opioids were now the leading cause of “injury-related mortality” in the United States, largely because of the wider use of the drugs in households nationwide. In 2012, doctors wrote <a href="http://www.cdc.gov/vitalsigns/opioid-prescribing/" style="color: #326891;">259 million prescriptions</a> for opioid painkillers.</div>
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“The medical community needs to develop a safety plan for parents to store the pills and make their homes safe for their children,” Dr. Gaither said. “Physicians prescribing medications to an adult, or even a teen, need to ask if there are younger kids in the household and, if so, to make sure they know how potent the drugs are and to keep them out of reach of kids.”</div>
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Dr. Gaither said the pills should be more securely packaged and better labeled.</div>
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“Oftentimes, parents are not told what to do with leftover medication, and that means it is left sitting around your house where your kids can find them,” said Sarah Clark, a co-director of the C. S. Mott Children’s Hospital National Poll on Children’s Health.</div>
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In a C. S. Mott <a href="https://www.ncadd.org/blogs/in-the-news/many-parents-keep-children-s-leftover-prescription-opioids-at-home" style="color: #326891;">poll</a> this year of nearly 1,200 parents with at least one child between 5 and 17, about one-third of parents said their children had been given prescriptions for opioids, and nearly half had leftover medication. Only 8 percent said they had returned the unused medication to a pharmacy or doctor. Forty-seven percent kept the leftover drugs at home; 30 percent threw them in the trash or flushed them down the toilet; 6 percent said other family members had used the leftover medication; and 9 percent did not remember what they had done with the rest of the medication.</div>
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“Most doctors don’t talk about the dangers of opioids and children,” Ms. Clark said. “We are really leaving it up to the parents’ initiative to solve this problem, and most parents are not medical experts. I would love to see the health care community step up and say let’s be more proactive about dealing with leftover medication.”</div>
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Jen Simon, a freelance writer in the New York City area who has <a href="http://jensimonwriter.com/" style="color: #326891;">written</a>about her addiction to painkillers, said that she had never been told how to dispose of leftover prescription medication, and that her doctors had never cautioned her about the dangers of opioids if ingested by her two young children.</div>
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“And my doctors know I have young children — they have been to my medical appointments with me,” Ms. Simon said.</div>
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Dr. Richard N. Rosenthal, a professor of psychiatry and an addiction psychiatrist at the Icahn School of Medicine at Mount Sinai in New York, said doctors needed to be properly trained on how to counsel patients who were being prescribed opioids on all aspects, including proper disposal of leftover medication.</div>
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“Opioids can be a ticking time bomb in your medicine cabinet,” Dr. Rosenthal said, adding that overprescribing of medications must also be addressed.</div>
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“Doctors should only prescribe what is necessary to take care of short-term acute pain,” he said. “You can always go back to your doctor if you feel you need more, but you should not take home more pills than needed.”</div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-30156680127043556012016-11-05T14:37:00.001-07:002016-11-05T14:37:13.848-07:00Two Drugs for Adult Migraines May Not Help Children<header class="story-header" id="story-header" style="margin-left: 0px; margin-right: 0px; position: relative;"><div class="story-meta " id="story-meta" style="margin-bottom: 20px;">
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<span class="byline" itemid="http://www.nytimes.com/by/catherine-saint-louis" itemprop="author creator" itemscope="" itemtype="http://schema.org/Person" style="font-family: nyt-cheltenham-sh, georgia, "times new roman", times, serif; font-size: 0.6875rem; font-weight: 700; line-height: 0.75rem; margin-right: 12px;">By <a href="http://www.nytimes.com/by/catherine-saint-louis" style="color: black; text-decoration: none;" title="More Articles by CATHERINE SAINT LOUIS"><span class="byline-author" data-byline-name="CATHERINE SAINT LOUIS" data-twitter-handle="cslnyt" itemprop="name" style="white-space: nowrap;">CATHERINE SAINT LOUIS</span></a></span><time class="dateline" content="2016-10-28T12:50:36-04:00" datetime="2016-10-28T12:50:36-04:00" itemprop="dateModified" style="font-family: nyt-cheltenham-sh, georgia, "times new roman", times, serif; font-size: 0.6875rem; line-height: 0.75rem; margin-left: 0px; white-space: nowrap;">OCT. 27, 2016</time></div>
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<figure aria-label="media" class="media photo lede layout-large-horizontal" data-media-action="modal" id="media-100000004733630" itemid="https://static01.nyt.com/images/2016/10/28/science/28MIGRAINE/28MIGRAINE-master768.jpg" itemprop="associatedMedia" itemscope="" itemtype="http://schema.org/ImageObject" role="group" style="clear: both; display: flex; flex-direction: column; margin: 0px 0px 45px; position: relative; width: 705px;"><span class="visually-hidden" style="border: 0px; clip: rect(0px 0px 0px 0px); height: 1px; margin: -1px; overflow: hidden; padding: 0px; position: absolute; width: 1px;">Photo</span><div class="image" style="cursor: pointer; flex-shrink: 0; margin-bottom: 7px; position: relative;">
<img alt="" class="media-viewer-candidate" data-mediaviewer-caption="Amitriptyline, a drug used to prevent migraines in adults, was not more effective than a placebo against the condition in children, a large trial found." data-mediaviewer-credit="Carolyn A. McKeone/Science Source" data-mediaviewer-src="https://static01.nyt.com/images/2016/10/28/science/28MIGRAINE/28MIGRAINE-superJumbo.jpg" itemid="https://static01.nyt.com/images/2016/10/28/science/28MIGRAINE/28MIGRAINE-master768.jpg" itemprop="url" src="https://static01.nyt.com/images/2016/10/28/science/28MIGRAINE/28MIGRAINE-master768.jpg" style="display: block; height: auto; max-width: 100%; width: 705px;" /><div class="media-action-overlay" style="border-radius: 6px; border: 1px solid rgba(200, 200, 200, 0.8); bottom: 15px; cursor: pointer; left: 15px; opacity: 0; position: absolute; transition: opacity 0.2s ease-in; z-index: 5;">
<span class="icon sprite-icon" style="background-image: url("/assets/article/20161104-095752/images/sprite/sprite-no-repeat.svg"); background-position: -223px -139px; background-repeat: no-repeat; display: inline-block; height: 38px; line-height: 0; vertical-align: middle; width: 38px;"></span></div>
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<figcaption class="caption" itemprop="caption description" style="color: #666666; font-family: nyt-cheltenham-sh, georgia, "times new roman", times, serif; font-size: 0.8125rem; line-height: 1.0625rem; margin-left: 0px; margin-right: 0px; max-width: 630px;"><span class="caption-text">Amitriptyline, a drug used to prevent migraines in adults, was not more effective than a placebo against the condition in children, a large trial found.</span> <span class="credit" itemprop="copyrightHolder" style="color: #999999; display: inline-block; font-size: 0.6875rem; line-height: 1rem;"><span class="visually-hidden" style="border: 0px; clip: rect(0px 0px 0px 0px); height: 1px; margin: -1px; overflow: hidden; padding: 0px; position: absolute; width: 1px;">Credit</span>Carolyn A. McKeone/Science Source</span></figcaption></figure><div class="story-body-text story-content" data-para-count="198" data-total-count="198" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
Neither of the two drugs used most frequently to prevent migraines in children is more effective than a sugar pill, according to a study published on Thursday in <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1610384" style="color: #326891;" title="The new trial published in NEJM. ">The New England Journal of Medicine</a>.</div>
<div class="story-body-text story-content" data-para-count="215" data-total-count="413" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
Researchers stopped the large trial early, saying the evidence was clear even though the drugs — the antidepressant <a href="https://medlineplus.gov/druginfo/meds/a682388.html" style="color: #326891;">amitriptyline</a> and the <a class="meta-classifier" href="http://health.nytimes.com/health/guides/disease/epilepsy/overview.html?inline=nyt-classifier" style="color: #326891;" title="In-depth reference and news articles about Epilepsy.">epilepsy</a> drug <a href="https://medlineplus.gov/druginfo/meds/a697012.html" style="color: #326891;">topiramate</a> — had been shown to prevent migraines in adults.</div>
<div class="story-body-text story-content" data-para-count="262" data-total-count="675" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
“The medication didn’t perform as well as we thought it would, and the placebo performed better than you would think,” said Scott Powers, the lead author of the study and a director of the <a href="https://www.cincinnatichildrens.org/service/h/headache-center" style="color: #326891;">Headache Center</a> at Cincinnati Children’s Hospital Medical Center.</div>
<div class="story-body-text story-content" data-para-count="156" data-total-count="831" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
A <a href="http://www.nytimes.com/health/guides/disease/migraine/overview.html?8qa" style="color: #326891;">migraine</a> is a neurological illness characterized by pulsating <a class="meta-classifier" href="http://health.nytimes.com/health/guides/symptoms/headache/overview.html?inline=nyt-classifier" style="color: #326891;" title="In-depth reference and news articles about Headache.">headache</a>pain, sometimes accompanied by nausea, <a class="meta-classifier" href="http://health.nytimes.com/health/guides/symptoms/nausea-and-vomiting/overview.html?inline=nyt-classifier" style="color: #326891;" title="In-depth reference and news articles about Nausea and vomiting.">vomiting</a> and sensitivity to light and noise.</div>
<div class="story-body-text story-content" data-para-count="122" data-total-count="953" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3681416/" style="color: #326891;" title="A study in Pediatric Neurology. ">It’s a common childhood condition</a>. Up to 11 percent of 7- to 11-year-olds and 23 percent of 15-year-olds have migraines.</div>
<div class="story-body-text story-content" data-para-count="291" data-total-count="1244" id="story-continues-1" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
At 31 sites nationwide, 328 <a class="meta-classifier" href="http://health.nytimes.com/health/guides/disease/migraine/overview.html?inline=nyt-classifier" style="color: #326891;" title="In-depth reference and news articles about Migraine Headaches.">migraine</a> sufferers aged 8 to 17 were randomly assigned to take amitriptyline, topiramate or a placebo pill for 24 weeks. Patients with episodic migraines (fewer than 15 headache days a month) and chronic migraines (15 or more headache days a month) were included.</div>
<div class="story-body-text story-content" data-para-count="180" data-total-count="1424" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
The aim was to figure out which drug was more effective at reducing the number of headache days, and to gauge which one helped children to stop missing school or social activities.</div>
<div class="story-body-text story-content" data-para-count="379" data-total-count="1803" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
As it turned out, there was no significant difference among the groups: 61 percent of the placebo group reduced their headache days by 50 percent or more, compared with 52 percent of the children given amitriptyline and 55 percent of those who took topiramate. And there was no significant difference among the three groups in reducing the school days or other activities missed.</div>
<div class="story-body-text story-content" data-para-count="149" data-total-count="1952" style="font-family: georgia, "times new roman", times, serif; font-size: 1.0625rem; line-height: 1.625rem; margin-bottom: 1em; margin-left: 75px; max-width: none; width: 570px;">
<span style="font-size: 1.0625rem;"><br />One child on topiramate attempted suicide. Three taking amitriptyline had</span><span style="font-size: 1.0625rem;"> </span><a class="meta-classifier" href="http://health.nytimes.com/health/guides/symptoms/depression/overview.html?inline=nyt-classifier" style="color: #326891; font-size: 1.0625rem;" title="In-depth reference and news articles about Depression.">mood changes</a><span style="font-size: 1.0625rem;">; one told his mother he wanted to hurt himself, while another wrote suicide notes at school and was hospitalized.</span>The drugs also produced side effects in some children, such as fatigue, dry mouth, and tingling in their hands or feet. A few cases were more severe.</div>
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Because of the side effects, Dr. Powers and his colleagues questioned whether the benefits of either drug outweighed its risks.</div>
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In 2014, <a href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm391026.htm" style="color: #326891;" title="FDA approval of topiramate in 12 to 17 year olds with episodic migraines. ">the Food and Drug Administration approved topiramate</a> for the prevention of migraine headaches in adolescents 12 to 17 who had fewer than 15 headache days a month. In light of the new study, Dr. Powers said he hoped that the F.D.A. and doctors would re-examine that decision.</div>
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Other experts were not yet ready to give up on drug treatment.</div>
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“Am I now going to feel obligated to tell patients that these drugs are no better than a placebo? No,” said Dr. Eugene R. Schnitzler, a professor of neurology and pediatrics at Loyola University Chicago Stritch School of Medicine.</div>
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“I’ll simply say, ‘We have data in adults that it’s effective, but less convincing data in children and adolescents.’”</div>
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Even if the drugs are not effective for children over all, “that doesn’t mean for any one individual, a drug might not work,” said Dr. David Gloss, a neurologist and a methodologist for the <a href="https://www.aan.com/" style="color: #326891;">American Academy of Neurology</a>.</div>
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A team of physicians, including Dr. Gloss, is revising <a href="https://www.aan.com/uploadedFiles/Website_Library_Assets/Documents/2.Clinical_Guidelines/3.Browse_By_Status/4.Guidelines_Under_Development/Protocol%20Migraine.pdf" style="color: #326891;" title="American Academy of Neurology's proposal for revision.">the academy’s guidelines</a> on pediatric migraines and planning to assess nondrug approaches.</div>
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A <a href="https://www.ncbi.nlm.nih.gov/pubmed/24368463" style="color: #326891;">trial published</a> last year found that taking amitriptyline and learning coping skills in a cognitive behavioral therapy program more effectively reduced headache days for chronic sufferers ages 10 to 17 than the drug given with only basic headache education.</div>
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<span style="font-weight: 700;">Correction: October 28, 2016 </span><br /><div style="font-size: 1rem; line-height: 1.4375rem; margin-bottom: 1em;">
Because of an editing error, an earlier version of the headline with this article referred imprecisely to the study results. While a greater portion of the placebo group reduced their headache days by 50 percent or more compared with children given the drugs, the difference was not statistically significant.</div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-21911951799235342322016-11-05T14:32:00.001-07:002016-11-05T14:32:49.838-07:00How Technology is Disrupting Medical Device Manufacturing<div style="background-color: white; box-sizing: border-box; color: #3a3a3a; font-family: source-sans-pro; font-size: 15px; line-height: 21px; margin-bottom: 10px; padding-bottom: 10px;">
<a href="http://www.pharma-iq.com/medical-devices-and-diagnostics/articles/medical-devices-directives-and-standards" style="background-color: transparent; box-sizing: border-box; color: #126393; text-decoration: none;">Medical device</a> sales are booming, driven by <a href="http://www.pharma-iq.com/business-development/articles/top-10-disruptive-technologies-in-pharma" style="background-color: transparent; box-sizing: border-box; color: #126393; text-decoration: none;">technological advances</a> and the needs of an aging population. The medical device market is one of the strongest segments of the economy for U.S. manufacturers, a Manufacturers Alliance for Productivity and Innovation report shows. Demand for electromedical and medical equipment and supplies is strong, led by demand for devices for in vitro diagnostics, cardiology, orthopedics, diagnostic imaging and ophthalmics. The global market for medical devices will grow at 4.1 percent annually to 2020, reaching $477.5 billion at that time, projects Evaluate Ltd. As the market grows, new innovations are promoting a <a href="http://www.healthcaredive.com/news/global-home-healthcare-market-projected-to-grow-at-cagr-of-885-through-20/419613/" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">trend toward the integration</a> of medical devices and home healthcare systems. To meet this growing demand, medical manufacturing is adapting disruptive technologies that are reshaping manufacturing as a whole and displacing established practices. Here’s a look at some of the disruptive trends that are transforming medical manufacturing.</div>
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Robotics</h3>
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Robotics is reshaping medical manufacturing in two major ways. First, demand for medical robots forms a major component of a rise in robotics sales, which surged 16 percent in 2015 to $2.2 billion and will grow to <a href="http://ein.iconnect007.com/index.php/article/100451/service-robotics-sales-up-25-boom-expected-by-2019/100454/?skin=ein" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">$22 billion by 2019</a>. The biggest contributor to this growth is sales of medical robots for tasks including diagnostics, surgical assistance and rehabilitation. Sales value of medical robots is projected to grow to $7.2 billion.</div>
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Meanwhile, robots are revolutionizing manufacturing itself, including the manufacturing of medical devices. 59 percent of manufacturers are already using robotics to some degree, a PricewaterhouseCoopers survey found. Today’s robots are nimble enough to assemble small parts, flexible enough to handle a variety of tasks rather than being dedicated to a single task and increasingly less expensive. Medical device manufacturers are finding the flexibility of <a href="http://www.qmed.com/mpmn/article/robots-help-manufacturers-flex-their-assembly-muscles" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">multi-tasking robots</a> useful for assembling hard-to-handle components, accelerating production and cutting costs.</div>
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Materials Science</h3>
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Materials science, the discipline that applies science to the development of new materials, is another transformative influence on medical manufacturing. As developments in fields such as nanotechnology, chemistry and biomaterials have given manufacturers greater ability to create customized materials, medical manufacturing has benefited. For example, medical engineers have developed biomaterials from synthetic, natural plant and animal and hybrid sources for use in medical devices. One example is the use of implantable biosensors for the early detection of diabetes. University of Washington engineers have been developing a<a href="http://www.washington.edu/news/2013/05/14/engineered-biomaterial-could-improve-success-of-medical-implants/" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">synthetic biomaterial</a> that can prevent the body from rejecting implanted objects.</div>
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3-D Printing</h3>
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3-D printing is another transformative technology reshaping medical manufacturing. 3-D printing is making it possible to create more customized medical devices for specialized applications. For instance, prosthetic knees must currently be manufactured in several different sizes and brought to hospitals for size selection before surgery. Then, the kits must be returned and re-sterilized before reuse. 3-D printing can enable custom knees to be specified to the fit of the individual patient. O-ring manufacturer <a href="http://www.applerubber.com/oring-size-search/" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">Apple Rubber</a> uses 3-D printing to manufacture a selection of over 7,000 customized medical o-rings.</div>
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Rapid Prototyping</h3>
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One important application of 3-D printing for medical manufacturers is rapid prototyping, which uses 3-D computer modeling to create digital prototypes which can then be produced with 3-D printing. 3-D printing is the future of rapid prototyping, says Med Device Online executive editor Jim Pomager. By applying 3-D printing to rapid prototyping, manufacturers can create prototypes much more quickly and cheaply than with traditional methods, reducing the amount of time needed to bring products to market. For example, medical manufacturer Stratasys uses rapid prototyping to test device design on realistic anatomical models.</div>
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Cloud Technology</h3>
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One of today’s most pervasive technologies is the cloud, which keeps millions of medical devices connected in cyberspace as part of the Internet of Things. Cloud usage in manufacturing and engineering will triple in 2017, participants in the Manufacturing ISV Cloud Summit projected. The cloud enables medical manufacturers to build products such as trackable mobile biosensors and remote imaging equipment. For example, Nuance’s PowerShare Network enables healthcare providers and patients to <a href="http://www.nuance.com/products/powershare-medical-image-exchange/index.htm" style="background-color: transparent; box-sizing: border-box; color: #5597b2; text-decoration: none;">remotely share images</a> in real-time over the cloud. Cloud tools such as Oracle’s Manufacturing Cloud also enable medical manufacturers to remotely supervise and track manufacturing processes.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com10tag:blogger.com,1999:blog-2150866002029873548.post-33576201474238506502016-10-19T02:56:00.001-07:002016-10-19T02:56:26.373-07:00Mass Measurement Precision of Small Objects in Pharmaceutical Production<div class="p1" style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25;">
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Unlocking the regulations-related advantages when using the new generation of contactless measurement systems</h2>
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By Arek Druzdzel and Arne Wieneke, Aiger Group AG, Zug, Switzerland</div>
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Jul 25, 2016</div>
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Traditional methods of weight measurement are based on comparison with standards accepted in designated areas. Over the past 200 years, a kilogram became such a standard and a metric base unit [1]. In the International System of Units (SI), it is defined as a mass standard and is used as a base for weight measurements worldwide.</div>
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Nowadays, with using the standard kilogram, it is expected it yields the same reading of high-precision weighing devices all over the world. As long as single measurements under laboratory conditions are at stake, using a standard mass in calibration procedures on state-of-the-art load cells is sufficiently precise as they allow for achieving highly repeatable and precise measurements.</div>
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However, load cells maintenance and calibration become a disadvantage when fast, precise and accurate measurements of single milligrams and micrograms are applied in-process production. It is a known fact, that under such conditions, scales have their limitations and correct adherence to regulations and production targets might not be ensured at the same time.</div>
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At first, scales with load cells require adjustment to the geographical location, otherwise the measured weight yields an error dependent on the actual location. In fact, scales do not measure mass but weight which is then translated into mass taking into account the locational gravity force.</div>
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Mass-reading error is caused by variation in the gravitational acceleration and the resulting gravity force (weight) that are not constant around the world.</div>
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The mass-reading error is caused by variation in the gravitational acceleration and the resulting gravity force (weight) that are not constant around the world. For an object of a given constant mass, its actual weight depends on both latitude and altitude of the actual location of the balance used for the measurement. Diagram 1 shows the variation in the gravitational acceleration around the world, at a constant altitude of 100 meters.</div>
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The gravitational acceleration at the Equator amounts to approximately 9.78 [m/s2], while at the poles it is approximately 9.832 [m/s2], resulting in discrepancy of 0.052 [m/s2], i.e. 0.53%.</div>
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Additionally, gravitational acceleration is affected by local altitude, tilt of Earth’s rotational axis, precession, equatorial bulge, etc. [2]. Gravity-related effects apply when, e.g. calibrating weight measurement devices to a mass standard, hence the more accurate and precise the measurement is required, the more time and effort are required both for calibration and the actual measurement. Furthermore, measurement precision and accuracy of scales and load cells changes with time from the last calibration, as they depend on elastic properties of materials in load cells, environmental conditions, and other components of a weighing system [4, 5]. </div>
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This discrepancy implicates variation in weight readings when an object of a given mass is measured at various latitudes and altitudes. Scales compensate this significant error by providing reference masses for pre-calibration. Evidentially, this calibration becomes critical when fast measuring small masses, e.g. in milligrams range; leading to more frequent calibration to ensure reliable measurement in line with regulations.</div>
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When now moving away from the perfect laboratory environment to the real production environment, more factors influence the weight measurement of small masses. Machines vibrate which cause slow measurements and/or potentially incorrect readings; potent products require contained handling inside RABS or isolators which require constant ventilation; products may vary in water content during processing whereas the dry weight is in focus, etc. Accumulation of these influencing factors limits the useable range of accuracy of load cells or even does not permit determining small masses accurately, precisely and quickly.</div>
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Furthermore, closed processes add and/or mix substances in a way that does not permit to monitor the correct execution of adding or mixing, because the process is closed or continuous. Such applications may not allow the use of load cells but only offline sampling or indirect estimation of weight. In particular, for continuous manufacturing, the offline monitoring of small weights is not an option – because it represents a time delay. In case of frequent sampling, “offline” is described as “inline” though it is not “online.”</div>
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<strong style="box-sizing: inherit;">Removing gravity and ambience from the equation</strong></div>
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A solution to the above described discrepancies is a highly time-stable, gravity-independent measurement system, capable of measuring the mass of objects online, i.e. the amount of substance instead of weight of fast-moving objects, e.g. capsules, tablets or powder. Such measurements would be identical around the world and independent of the influencing factors, allowing not only for tight and online monitoring of substances but also direct data comparison.</div>
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Over the past years, we have developed such a novel system [3] and successfully installed it in a number of factories around the world. The system uses sensors emitting a local energy field directly interacting with the substance passing through the field and this way, alternating its output signal. As a result of such a field-substance interaction, the initial (empty sensor) signal changes adequately, creating an output signal. Such modified signal is equivalent to the amount of the substance passing through the measurement system. Once measured, the signal can be instantly converted to mass or the local weight. Knowing exactly the quantity of the substance dosed, i.e. mass of an object, the whole dosing-measuring system is automatically calibrated to the weight measurable in any region (location) where it is destined, without a need for overdosing or a risk of underdosing.</div>
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As only the substance change the output signal, the signal is ambience-independent, allowing for online, positive process control. As sensor signal data processing is fast enough, it allows for closed loop control.</div>
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<strong style="box-sizing: inherit;">A new industrial application</strong></div>
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An industrial version of such a system has been built and verified with a variety of small objects, including capsules in 4 to 00 size range, tablets as well as with micro-dosing of powder from 1mg to 500mg into vials and syringes. The system requires just a single push-button calibration that once done at a location, does not need any further recalibration services. The system has proven stable precision and accuracy within one sigma ranging from 0.25% to 3%, the dispersion depending mainly on materials structure and morphology.</div>
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Most important for production environments, the proposed system ensures quick, precise and accurate mass measurement of a very wide range of objects, with no need for major system adjustment, special environmental conditions, leveling, isolation from vibration and ventilation or prolonged measuring time. The system has no moving or flexing elements hence it is free from disadvantages associated with common weight measurement systems.</div>
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With already initiated transition of the pharmaceutical industry from batch production to continuous manufacturing, such a system is an important and highly anticipated tool for reliable monitoring quantities of smallest ingredients and finite products.</div>
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There are well-known shortcomings of customary, online weight measurements systems, especially for industrial applications in the pharmaceutical industry. However, alternative system for online, precise and accurate measurement of small masses are available.</div>
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The gravity-independent and highly effective mass measurement system facilitates compliance with existing drug quality regulations as well as with the industry safety directives and guidelines for cGMP, QbD and PAT. It does provide the capability to reduce cost but most importantly, it enables extension of products serialization down to formulation and components level and streamlines industrialization processes.</div>
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<strong style="box-sizing: inherit;">References</strong></div>
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<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0px;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Kilogram – the base unit of mass, Wikipedia</span></li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Earth’s rotation, Wikipedia</span></li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Patent application GB2512026A</span></li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Pharmacopeia USP General Chapter 41 and 1251</span></li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">European directive 2009/23/EC</span></li>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-39399009931048100852016-10-19T02:54:00.004-07:002016-10-19T02:54:59.677-07:00Transparency: A Vital Ingredient for Safe, Effective Medicines<div style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25;">
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By making the cloud the heart of their networks, companies are adapting quality systems to address supply chain risks</h2>
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By Michael Jovanis, Veeva Systems</div>
There’s no question that pharmaceutical and medical device production has become more complex, especially with the growing number of biologics and combination products. These products come with their own set of complicated production challenges and supply chain risks. As life sciences companies outsource to better scale and contain costs, complexity only increases. With more manufacturing functions externalized — and outside of direct oversight — ensuring continuity of processes, regulatory compliance, and accurate, high-quality data from start to finish is difficult.</div>
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“It used to be that if a company did any outsourcing, it was primarily limited to sourcing raw materials,” said Daniel Matlis, founder and president of Axendia, a life sciences industry analyst firm. “But as a compounding number of companies began to go outside their four walls, they discovered opportunities to reduce cost and shed non-core competencies. Now, many aspects of manufacturing are handled by contract organizations.”</div>
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</aside><span style="background-color: white; font-family: "texgyreheros" , "arial" , sans-serif; font-size: 14px;">As the supply chain expands, it’s absolutely essential for companies to maintain complete visibility with contract manufacturing organizations (CMOs) on good manufacturing practices (GMP), quality processes and data. Further, life sciences companies should make it standard operating procedure to carefully review GMP data generated by CMOs so they have the insights they need before approving batch lots for release. All too often, companies don’t have easy (or any) direct access to CMOs’ systems and so often skip this important step.</span><br />
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Demand for manufacturing outsourcing has grown steadily, from $800 million in 1998, to $2.5 billion in 2014 and is expected to reach $4.1 billion by 2019, according to a recent survey on contract manufacturing from High Tech Business Decisions. Today, the U.S. is the largest market for contract manufacturing worldwide. In total, 80 percent of the active pharmaceutical ingredients consumed in the U.S. originate in India and China, and about 40 percent of the finished products come from outside the U.S. Europe lags slightly behind, but growth is expected from developing regions such as Asia Pacific, with the Japanese market projected to register a compounded annual growth rate of 13 percent.1</div>
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That’s the good news, but increased outsourcing also adds several degrees of complexity to an already complicated process. As life sciences companies relinquish a level of control over the manufacturing process in return for lower costs, they open the door to diminished transparency. Without worldwide supply chain visibility, quality can suffer. In fact, a number of popular prescription drug products manufactured in India were recently banned from U.S. importation due to quality concerns — these include acne treatment Accutane and the antibiotic Cipro. These issues continue to grow, driving the U.S. Food and Drug Administration to increase its local presence throughout the world.<br />
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“We now have offices and inspectors in New Delhi and Mumbai, India, as well as China, Latin America, South Africa and a growing cadre of international inspectors elsewhere,” said Dr. Margaret Hamburg, former commissioner of the FDA, during a 2014 interview. “We’re trying to achieve the same levels of inspection, enforcement and compliance that we would expect of any company manufacturing drugs for consumption by the American public,” Hamburg said.2</div>
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“Unfortunately for the life sciences industry, there have been a number of challenges associated with contract organizations, which has put a finer focus on the need for control and visibility into what happens at suppliers,” said Matlis. “Regulators are well aware of this situation.” In fact, of the 20 warning letters issued by the FDA Center for Drug Evaluation and Research Office (CDER) of Manufacturing Quality in 2015 — more than half were related to cGMP.</div>
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Despite the government effort, manufacturers are still dealing with tragic manufacturing errors that are not always discovered until it’s too late. For example, Heparin, a popular blood thinner manufactured in China, was contaminated by someone upstream in the supply chain. A cheaper, incorrect active ingredient that tested just like the right active ingredient was substituted in the manufacturing process. The drug made it into the U.S. supply chain, causing a large number of patients to become ill.4</div>
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Vigilant supply chain visibility is the key. It provides the crucial system of checks and balances that often go missing when a company moves critical stages of its manufacturing process to outside vendors. As the supply chain becomes more complex and thus more risky, companies are finding that they need to adapt their quality systems to address these risks.<br />
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<strong style="box-sizing: inherit;">TROUBLE WITHOUT TRANSPARENCY</strong><br />
For life sciences companies, transparency means visibility into the manufacturing process, timely access to data and content, and an accurate audit trail of all activities. Often, companies do not learn about issues that can hinder the delivery of a finished product until it is too late either because the supplier is trying to resolve the problem on its own or the manufacturer is never made aware. Life sciences companies try to prevent problems by maintaining frequent communications with contracted organizations, often via phone or email, but this is not practical, sustainable or secure.3 When exchanges of vital information between companies and CMOs rely on paper-based and manual processes that involve many people reading and transcribing emails and faxes — errors are bound to occur. As problematic, there is no consolidated audit trial of these exchanges, making it nearly impossible to confirm and manage.</div>
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The troubling reality is that process gaps and inaccurate or incomplete data can lead to products that do not meet health authority standards for safety, purity or efficacy. In addition to threatening the safety of medications, poor data quality can create costly, time-consuming bottlenecks in the drug development process…and, ultimately, dangerous drug shortages.</div>
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The negative consequences of fragmented quality processes, poor data quality and lack of transparency are even more acute when a healthcare authority sends a warning letter to a company stating that its manufacturing processes, or those of its CMO, do not meet regulatory requirements. From 2007 to 2013, the number of warning letters issued by the FDA increased by 78 percent, with this number expected to increase in the coming years.4 After receiving an FDA Form 483 at the conclusion of an inspection, a company can continue manufacturing, but it is given specific instructions on steps it must take to correct problems. The FDA’s more severe Consent Decree letter can order a company to stop manufacturing altogether or order it to shut down a particular facility. Either notification usually requires that a manufacturer evaluate and revamp processes, resulting in devastating cost and time losses. In the end, it delays time to market — which can cost companies up to $8 million a day, according to various sources.</div>
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Not only can these warnings cause serious financial losses for life sciences companies, but also can dramatically erode public trust, impacting the brand and corporate reputation in confounding ways.</div>
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<strong style="box-sizing: inherit;">OUTSOURCE MANUFACTURING, NOT RESPONSIBILITY</strong><br />
Life sciences companies can outsource their processes, but not responsibility for quality. According to the International Council for Harmonization (ICH), “The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials.”5</div>
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The EU legislation for the pharmaceutical section, guidance contained within EudraLex, reaffirms this standpoint: “The contract giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities.”6 And, in the U.S., the FDA regards contract facilities “as an extension of the manufacturer’s own facility and therefore expects a company’s supplier network to perform as an extension of its own quality system. The FDA also states that “the owner’s quality unit is ultimately responsible for approving and rejecting drug product manufactured by the contract manufacturer.”7</div>
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The FDA is proposing to standardize quality metrics — defined as “objective measures of the quality of a product or process” — as a tool to evaluate drug manufacturers and compare quality results between similar companies and products. The FDA plans to capture data from manufacturers over a one-year period for lots attempted, lots rejected, lots with out-of-specification results, stability tests conducted, and the number of quality complaints. After the data is compiled, the FDA says that it will use this aggregated data to generate metrics to arrive at an objective measure of quality.⁸</div>
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“Now that companies are dealing with a global and outsourced environment, they need to truly characterize their products uniformly and to scientifically understand what are the critical-to-quality (CTQ) attributes essential to producing the desired outcomes. Just as important is the master data, which needs to be properly defined, curated and managed. Finally, everything — the documents, the data, the SOPs — needs to be totally transparent. This is the direction of regulators as well,” said Matlis.</div>
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Visibility is possible with the right technology. It starts with a hyper-connective network that links multiple partners in a fluid, cloud environment. Having continuous processes and timely access to data all along the supply chain fosters collaboration and transparency among the company, outsourced manufacturers and suppliers globally. This opens up the ability to measure processes, ensure compliance standards are met and quality standards are exceeded. Companies can then reduce risk, find anomalies or opportunities for improvement, and act upon them quickly.</div>
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Yet, while 90 percent of companies have implemented at least one quality management system, they often reside within and are only accessible within a company’s internal network.9 Such on-premise solutions do not easily allow appropriate levels of access to those who need it most, including most especially, contract partners. As companies outsource more, everyone — brand owners, suppliers and CMOs — need complete access and, therefore, visibility to the most current, accurate information available. This is data transparency, and it is the key to quality.</div>
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<strong style="box-sizing: inherit;">THE CLOUD MAKES QUALITY CLEAR</strong><br />
Using cloud-based technology to orchestrate drug development and manufacturing enables seamless processes and provides all stakeholders with access to accurate data and content in a single, authoritative system. It also enables partners to be a part of the process — offering input, contributing data and improving the entire operation. Most crucially, the cloud solution should extend enterprise-wide, from end to end, to ensure that all relevant data is captured reliably across the organization because there is just one source of truth.</div>
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The cloud gives life sciences companies the ability to extend visibility across all parts of the value chain, while at the same time enabling partners to access information they need to provide valuable services. Raw materials suppliers, CROs, CMOs, brokers and distributors can interact simultaneously under very controlled conditions that ensure up-to-date information is always available to those that need it — whenever, wherever, however they need it.</div>
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“Providing our partners with direct access to our validated, cloud-based quality system ensures we maintain a clear chain-of-custody on manufacturing documents such as batch records and audit reports,” explained Craig Gassman, associate director of regulatory operations at Karyopharm Therapeutics — a clinical-stage pharmaceutical company focused on discovery and development and subsequent commercialization of novel first-in-class drugs directed against nuclear transport and related targets for the treatment of cancer and other major diseases.</div>
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Modern solutions also enable life sciences companies to gain real-time visibility into the status of quality processes. Workflows can be set up to allow both internal staff and outsourced partners to view important data or content uploaded by either party all in one place — again, for a single source of truth. Seamless processes and comprehensive views prevent breaks in the audit trail that cause mistakes, quality control issues and even FDA observations. For example, the operations team can set alerts for people in the workflow and the entire team can see who performed tasks and when. This close collaboration is essential for efficiency and quality. In clinical trials, for instance, cloud applications speed the collection of all trial-related content, providing status updates throughout a study’s start-up, execution and close.</div>
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<strong style="box-sizing: inherit;">MANAGING PROCESSES, DATA</strong><br />
In manufacturing, with greater outsourcing of critical functions, companies are starting to rely on cloud solutions to manage quality processes and keep track of data received from contract test labs, manufacturers and other specialty partners. Key people can easily review executed batch records from anywhere before acceptance and release of product. Deviations and subsequent communications are also centrally tracked and visible to all parties. Increasing efficiency while improving compliance and quality results in fewer inspections, faster inspections and significant reduction in risk of receiving warning letters or forcing dreaded plant shutdowns.</div>
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“In this outsourced environment, it becomes very difficult to manage operations using ‘tribal knowledge,’ that is, bringing in a person or a group of people who really understand a step or process or molecule and getting their opinion to address an issue,” said Matlis. “Once a life sciences company establishes quality attributes critical for each product and the requisite data that needs to be managed, it must implement solutions that not only manage quality, but even more important, improve quality.8</div>
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The key to solving these challenges is a shift in the underpinnings of the life sciences supply chain. It’s time to operate the business as a broader network that allows suppliers and partners to become directly tied into the central nervous system of the life sciences company. To do so effectively, organizations are making the cloud the heart of that network — and, with greater visibility, successfully retaking full responsibility for the quality of their products.<br />
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<strong style="box-sizing: inherit;">SOURCES</strong><br />
<em style="box-sizing: inherit;">1. “Achieving Global Supply Chain Visibility, Control & Collaboration in Life Sciences: Regulatory Necessity, Business Imperative,” Axendia, 2010. p.7</em><br />
<em style="box-sizing: inherit;">2. “The Safety of Prescription Drugs Made Outside the U.S.,” The Diane Rehme Show, February 20, 2014. </em><br />
<em style="box-sizing: inherit;">3. “Measuring the Business Value of Data Quality,” Gartner, 2011. </em><br />
<em style="box-sizing: inherit;">4. “FDA Warning Letters Rise 78% Over Six Years with Increase Expected in 2015,” The Pharma Letter, 2014. </em><br />
<em style="box-sizing: inherit;">5. “ICH Harmonised Tripartite Guideline: Pharmaceutical Quality System Q10,” International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2008. </em><br />
<em style="box-sizing: inherit;">6. Eudralex Volume 4 Chapter 7, Outsourced Activities</em><br />
<em style="box-sizing: inherit;">7. 21 CFR 200.10</em><br />
<em style="box-sizing: inherit;">8. “Quality Metrics: What Does It Really Mean?” Contract Pharma, 2016. </em><br />
<em style="box-sizing: inherit;">9. FY17-Mfg-Managing External Quality</em></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-58857664859393861972016-10-19T02:53:00.001-07:002016-10-19T02:53:28.157-07:00Holding the Diagnostic Mirror<hgroup style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px;"><h2 class="deck" style="box-sizing: inherit; color: #838383; font-family: Verdana, Arial, Helvetica, sans-serif; font-size: 1.4rem; font-weight: normal; line-height: 1.2; margin: 3px 0px 0px;">
Only those pharma companies with enough courage and imagination to learn and apply lessons from other industry leaders can hope to break from the pack</h2>
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By Thibaut Dedeurwaerder and Jonathan Tilley, McKinsey & Company</div>
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Pharma managers should learn to watch their operations differently, see opportunities for improvement on their shop floor, and learn from top-performing peers and from leaders in other industries how to capture these opportunities.<br style="box-sizing: inherit;" /><br style="box-sizing: inherit;" />The pharmaceutical industry is lagging other industries in operational efficiency, as indicated by OEE ranges of 10-60 percent, up to six-month lead times, and other measures. Few pharma managers understand shop-floor operations and their potential for improvement, and few learn from their industry peers — even those whose performance is far superior. But even the best-performing pharmaceutical plant is miles away from the efficiency achieved at the average Toyota plant. Only those pharmaceutical companies and plants with enough courage and imagination to learn and apply lessons from other industry leaders can hope to break from the pack.</div>
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<strong style="box-sizing: inherit;">DIAGNOSING BY "GENCHI GENBUTSU"</strong><br style="box-sizing: inherit;" />When Taichi Ohno, Toyota’s head of production engineering after the second world war, visited Ford’s plants in Michigan, he may have been impressed by what he saw in the industry leader’s facilities. But beyond understanding the manufacturing system, he found many areas for improvement on the production line, such as a leveled pace of production and a smaller work-in-progress inventory. His visit, and the knowledge he took back to Japan, show how looking at systems or processes with fresh eyes can reveal new insights at the most basic level. This is exactly what pharmaceutical companies need to do now to uncover opportunities for improvement in operations.</div>
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This type of visit offers several lessons. Years before Toyota codified its core manufacturing principles, Mr. Ohno had already found new approaches to looking at production processes. The principle was “Genchi Genbutsu” — go and see for yourself. Managers watch processes, in person, to understand the fundamentals of what adds value and what does not. This approach would later become one of Toyota’s most famous slogans, and it is fundamental to production process diagnostics.</div>
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No matter how good their information, pharma managers rarely find inefficiencies in operations behind a desk. Yet all too often, managers accept the data in front of them without challenge. Anybody who wants to know what really goes on in manufacturing, including people’s difficulties and daily worries, must go to the shop floor and look, listen, question and understand.</div>
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We find that many pharma managers get wrapped up in other areas and fail to understand how much value can be added. They spend too little time watching operations or meeting and talking with employees. People on the shop floor often tell us that managers seem uncomfortable during visits. Not sure how they should behave, what they should be looking for or asking, many managers are actually relieved when they can return to the safety of their offices.</div>
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<strong style="box-sizing: inherit;">WHAT SHOULD THEY BE LEARNING?</strong><br style="box-sizing: inherit;" />Pharmaceutical managers need to “learn to see” waste and variability in familiar processes, rather than just the barriers to change. Managers must ask “what would it take” rather than simply report “why we can’t do it.” Looking for waste and variability, especially in your own operations, requires courage. It also requires observation. In more than 50 plant walks and diagnostics we have conducted, we have seen pharma executives gain tremendous insights and benefits.</div>
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When we brought pharma managers to the shop floor, we sometimes found that less than half the equipment was running, and that multiple weeks of work in progress (WIP) was stored in many different places. On other occasions, we found different operators working on the same equipment with no clear work descriptions, and saw for ourselves the heavy burdens of batch documentation.</div>
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Results from these diagnostics speak for themselves: Many plants can improve their productivity and throughput times by 30 percent, and some by 50 percent.</div>
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<strong style="box-sizing: inherit;">LEADING PHARMA PLANTS' BEST PRACTICES</strong><br style="box-sizing: inherit;" />Some pharma plants perform up to 20 times better than their lowest-performing peers, according to POBOS benchmarks for over 200 facilities. What distinguishes the top performers?</div>
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What we notice first when visiting top performing plants is the activity on the shop floor. Paradoxically, it is relatively low! Corridors are lonely, lines are populated sparingly and people aren’t running around. Multi-machine handling helps make this possible. But implementing this seemingly simple principle requires three enablers that distinguish top performers:</div>
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• Machine effectiveness at top-performing plants is significantly higher, with OEEs as high as 60 percent. Lines have fewer minor stops and breakdowns; product changeovers are executed efficiently; lines are run at a speed that meets the targeted output and quality. Underlying high machine effectiveness is a problem-solving approach where production operators, maintenance technicians and engineers collaborate in the pursuit of continuous improvement. Line performance is monitored systematically and continuously. Where a gap appears between planned and actual performance, the team responds immediately by looking for the root cause and implementing countermeasures.</div>
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• Efficient workplace design also plays a key role. Good plant layout enables multi-tasking. This includes a minimum of physical barriers on the shop floor to allow operators to flow between areas (e.g., automatic doors, same clean room classification throughout production). Line operators at top plants have all they need at arm’s length, and work stations are close to each other to reduce walking and searching time.</div>
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• Elimination of non-value-adding activities. Obviously, high machine effectiveness and efficient workplace design help reduce non-value added activities like repairing, waiting and walking. But top performers push it further. For example, by adopting the “critical to quality” principle, they reduce documentation by limiting the number of inputs to the items that really matter for product quality. Beyond removing non-value adding tasks, they also try to simplify activities. Fewer and simpler tasks mean fewer mistakes. The number and frequency of in-process controls are reduced to what is appropriate based on the process need and knowledge, rather than habit or tradition.</div>
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Many top performers have also reduced non-value-adding activities by investing in automation, such as automatic weighing stations and guided vehicles, container-washing machines and electronic batch records. The distinctiveness here, however, lies not so much in the investments but in the way the automation and systems are selected and implemented. Top performers understand that automation in itself does not guarantee performance or productivity. For any automation investment, they require a clear business case that is reviewed in a thorough capex approval process. Also, any process to be automated is optimized in-depth before being automated to avoid “locking in” inefficiencies.</div>
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Another characteristic that distinguishes top-performing plants is the mindset of their leaders. Most recognize that pharma is no different from other industries that have applied lean concepts. A recurring challenge is the perception that lean principles are difficult to marry with pharmaceutical operations, because of the highly regulated nature of the industry.</div>
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But managers at high-performing plants find the lean journey does not expose them to undue risk — and can even offer the same kinds of benefits seen in other industries. On one hand, managers understand that productivity and efficiency do not have to compromise quality, and that simplified work processes can reduce complexity, non-value-added activity and opportunities for error. What’s more, with quality being one of the main functions in pharma plants, managers also understand how lean principles can have tremendous benefits when applied in the quality department itself.</div>
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<strong style="box-sizing: inherit;">HOW TOYOTA WOULD MAKE PILLS</strong><br style="box-sizing: inherit;" />Given the huge spread in performance, pharma plants can learn a lot from each other about how to run operations efficiently. But even the best-performing plants can raise their aspirations by looking critically for waste and variability in their operations. A key purpose of a diagnostic is to find the technical limits of “what would we have to do” to improve. Each company should aspire to be the “Toyota of the pharma industry.” Admittedly, cars are not pills or vaccines. But it is worth thinking about how Toyota might go about making pills; this insight guides how we look at a diagnostic.</div>
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When comparing a top-performing pharma plant with the production system at Toyota, questions immediately arise:</div>
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1. Why are line-OEEs below 90 percent?<br style="box-sizing: inherit;" />2. Why is throughput time 10 to 30 longer than actual process time?<br style="box-sizing: inherit;" />3. Why don’t all operators follow a standardized work pattern?</div>
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Pharma executives reply with rational-sounding explanations, such as that change-over times and campaign sizes limit the flow, they face quality constraints, and that unforeseeable events prevent further standardization of work.</div>
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<strong style="box-sizing: inherit;">LESSONS FROM AUTOMOTIVE</strong><br style="box-sizing: inherit;" />These explanations for inefficiency sound like those of automotive executives of 30 to 40 years ago. Yet today the car industry produces an exceptional variety of products in an ever more efficient way, with ever shorter delivery lead times and extremely high quality. Toyota assembles all the variants of more than one model on a single production line with a 97-99 percent run ratio (a kind of an OEE measurement), with virtually no buffer stocks, while achieving the best quality-performance in the industry, enabling them to offer five-year warranties in many markets.</div>
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It is reasonable to believe that Toyota would immediately address the poor OEE-levels of 10-60 percent in pharma. Just as automotive companies started to improve equipment effectiveness decades ago, pharmaceutical companies should now follow suit.</div>
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Toyota would not accept a product spending more than 30 days in a manufacturing facility. They aspire to get production down to pure processing time. Production would be controlled by pull to minimize work-in-process levels. Quality checks would be built into the process via error-proofing, and confirmation would be done in real time, leading to immediate release on receipt of any test needing incubation time.</div>
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Finally, by no means would Toyota allow non-standardized work execution. Standardized work is the basis of performance and improvement. Every process — be it a quality test, a changeover or a line replenishment — would be torn down to its basic elements. These would be sequenced and put onto a timeline, and managers would meticulously verify adherence to standards.</div>
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When Mr. Toyoda, former president of Toyota Europe, grandson of the founder and now the head of Toyota, visited the assembly plant in France a couple of years ago, he complained that operators did not follow standardized work processes. Indeed, during the plant tour, he stopped on the line, opened the standardized work manual for the position, and verified second-by-second that the operator performed the job according to its specified elements.</div>
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In what other industry does the head of the corporation take the time to investigate how a process is executed on the factory floor? Or pause long enough to ask why an operator handled a bolt with his right hand instead of his left?</div>
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What nobody thought possible in the automotive industry 50 years ago came true as one leader emerged. Pharmaceutical executives should aspire to excel on cost, service and quality and move away from the current “either-or” mindset.</div>
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Those with the courage to look firsthand at their operations — and the imagination to find the solutions to remove waste and variability from the processes and production system as a whole — will become leaders in their industry.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-90865003996594615022016-10-19T02:47:00.003-07:002016-10-19T02:47:33.867-07:00Next-Generation Innovation<div style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25;">
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Streamlined strategies secure pharma’s future as the industry thinks outside the pill box</h2>
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By Karen Langhauser, Chief Content Director</div>
As drug pricing reaches what some might argue is the height of public and political scrutiny (thanks Martin Shkreli), consumer expectations rise, and the blockbuster model continues its well-documented demise, the market has made innovation mandatory for the pharmaceutical industry. Bottom-lining it, PcW stated in its “<a href="https://www.pwc.com/gx/en/pharma-life-sciences/assets/pwc-managing-innovation-pharma.pdf" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">Managing Innovation in Pharma</a>” report, “the rewards for success are high and the risks of failure can threaten a company’s very survival.”</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">To say that the pharmaceutical industry lacks innovative ideas would be doing a tremendous disservice to an industry that has sustained decades of respectable growth along with a healthy list of historic medical achievements. More recently, the last five years of <a href="http://top100innovators.stateofinnovation.thomsonreuters.com/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">Thomson Reuters Top 100 Global Innovators</a> lists consistently report pharma as one of the largest industry sectors represented.</span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Rather than isolated examples of innovation in the form of single new molecules, today’s market calls for next-generation innovation in the form of innovation strategy.</span></div>
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Vetter has upgraded to implement an internally engineered restricted access barrier system to meet partners’ growing aseptic processing needs.</div>
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</aside><span style="background-color: white; font-family: "texgyreheros" , "arial" , sans-serif; font-size: 14px;">For many drug manufacturers, innovation strategy involves streamlining an increasingly complex manufacturing system. This type of next-generation innovation wades through the growing sea of new ideas and emerges with the strategies that deliver a clear, focused value. How does this play out in pharma in 2016? In the form of targeted acquisitions and partnerships, personalized treatments, efficient outsourcing partners and properly integrated technologies.</span><br />
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Delivering authentic innovation in today’s pharmaceutical environment is a momentously complex task with one very succinct emphasis. That emphasis, according to Dr. Clive Meanwell, CEO at <a href="http://www.themedicinescompany.com/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">The Medicines Company</a> and recent recipient of the 2016 Dr. Sol J. Barer Award for Vision, Innovation and Leadership, is a “sharp focus on what customers really need.” <span style="box-sizing: inherit;"><br style="box-sizing: inherit;" /></span></span></div>
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<strong style="box-sizing: inherit;">MERGERS, ACQUISITIONS AND PARTNERSHIPS</strong><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;"><a href="https://www.pwc.com/us/tophealthissues" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">PwC’s Health Research Institute’s annual report</a>predicts that 2016 will be the “year of merger mania” in healthcare, specifically mentioning the pharmaceutical and life sciences sector. According to the report, “drug companies are looking beyond traditional M&A by acquiring ‘beyond-the-pill’ products and services to bolster their portfolios and pipelines of drugs.”</span></div>
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Consolidation has typically been a dirty word in pharma and rarely appears in the same sentence as innovation. But a handful of forward-thinking companies are recognizing the need to innovate beyond merely acquiring new molecule formulations. Dwindling (though definitely not gone) are the days when pharmaceutical companies would hunt for deals to boost up specific therapeutic areas, aiming to completely dominate that space. Under immense pressure to optimize performance, today’s companies are taking a heavy look at the systems and services behind these new drugs and making strategic acquisitions with an eye toward innovative services and digital technology. </div>
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<span style="box-sizing: inherit;"> <span class="hs-cta-wrapper" id="hs-cta-wrapper-9a3b8485-5687-47f2-bf16-df909e3ddf3b" style="box-sizing: inherit;"><span class="hs-cta-node hs-cta-9a3b8485-5687-47f2-bf16-df909e3ddf3b" data-hs-drop="true" id="hs-cta-9a3b8485-5687-47f2-bf16-df909e3ddf3b" style="box-sizing: inherit; visibility: visible;"><a class="cta_button " cta_dest_link="http://info.pharmamanufacturing.com/150300-bestof-lp-0" href="http://cta-service-cms2.hubspot.com/ctas/v2/public/cs/c/?cta_guid=9b480748-0261-48b9-b9c8-8812be7b2405&placement_guid=9a3b8485-5687-47f2-bf16-df909e3ddf3b&portal_id=450121&redirect_url=APefjpHbdaXPzuJ30X12GanOiiuxIKewRBiIpR38inU-Sg8mBlq8fiWLlm1cSf0uBb7MbkPKjkOiSbeF2xwepa4VPJD0cJHl8pzUn4PkVr1IefxtoXELK_kcQoICuKpBkglluXk-qXp1oy3g_sWy6t4XKm1vAUqGbw&hsutk=&canon=http%3A%2F%2Fwww.pharmamanufacturing.com%2Farticles%2F2016%2Fnext-generation-innovation%2F&__hstc=16129577.550ff52f4695380adb188a355c888b5b.1476870359365.1476870359365.1476870359365.1&__hssc=16129577.1.1476870359366&__hsfp=634756348" id="cta_button_450121_9b480748-0261-48b9-b9c8-8812be7b2405" style="background: transparent; box-sizing: inherit; color: #ccad68; cursor: pointer !important; text-decoration: none;" target="_blank" title=">>>>>>Download the Pharmaceutical Manufacturing Top 5 eBooks Collection"><span style="box-sizing: inherit; color: #660000; font-family: "georgia" , serif; font-size: 26px; line-height: normal;">>>>>>>Download the Pharmaceutical Manufacturing Top 5 eBooks Collection</span> </a></span></span> </span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Teva Pharmaceutical made a strong move in the digital space in September with its <a href="http://www.pharmamanufacturing.com/industrynews/2015/teva-buys-mobile-health-startup/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;">purchase of smart inhaler company</a>, Gecko Health. Prior to that acquisition, Teva, in collaboration with Phillips Healthcare, launched Sanara Ventures in Israel. The collaboration will invest approximately $26 million to support 40-50 early-stage digital healthcare and medical device companies in the next eight years. </span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">The last few years have seen numerous innovative crossovers as pharma looks toward unconventional partnerships, specifically in the tech field. In 2014, Google’s R&D business, Calico, partnered with AbbVie to focus on age-related diseases. Around the same time, Google X Labs teamed with Novartis to develop glucose monitoring, smart contact lenses and early last year, partnered with Biogen to explore wearables technology in multiple sclerosis.</span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">But M&A is not always about innovation. Sometimes it’s about money — often in the form of tax inversion deals. The $160 billion dollar<a href="http://www.pharmamanufacturing.com/industrynews/2015/pfizer-and-allergan-merge-in-160b-deal/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;"> 2015 Pfizer-Allergan merger</a> created the world’s biggest drug company — and will move Pfizer’s domicile from the U.S. to Ireland, dropping its corporate tax rate by about 7-8% percent. Pfizer is not alone in capitalizing on this tactic. In 2014, <a href="http://www.pharmamanufacturing.com/industrynews/2014/mylan-to-acquire-abbott-labs-generic-drug-division/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;">Mylan acquired Abbott Labs</a> and moved its headquarters to the Netherlands. In 2014, AbbVie reconsidered its $54 billion acquisition of Shire — a deal that would have allowed AbbVie to reincorporate in Britain — after the Treasury Department announced new rules taking aim at inversion deals. According to a Bloomberg report, about 51 U.S. companies have reincorporated in low-tax countries since 1982, including 20 since 2012.</span></div>
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<strong style="box-sizing: inherit;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">TARGETED OUTSOURCING PARTNERS</span></strong><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">As their goal is to serve the unmet needs of the pharmaceutical and biotech industries, contract manufacturing movements are often reflective of the drug industry demands. Like the industries it serves, the contract services market has not been immune to consolidation. In fact, according to Visiongain’s<a href="https://www.visiongain.com/Report/1396/Pharmaceutical-Contract-Manufacturing-World-Industry-and-Market-Outlook-2015-2025" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank"> “Pharmaceutical Contract Manufacturing World Industry and Market Outlook 2015-2025</a>,” about 30 CMOs account for more than half of the industry’s revenues and, in the last three years, there have been 18 acquisitions in the CMO space.</span></div>
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Despite a reduction in supplier options, pharmaceutical manufacturers are becoming smarter and more specific when it comes to choosing contract manufacturing partners, expecting a higher degree of flexibility.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">According to Peter Soelkner, managing director at <a href="http://www.vetter-pharma.com/en/home-en" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">Vetter Pharma,</a> “drug companies are making every effort to reduce and simplify their network of different service providers. What they want to achieve, whenever possible, is a solution that equates to ‘one-stop-shopping.’ They expect that any partner they choose to work with must be strategic in their efforts, not simply tactical.”</span></div>
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Vetter is in the process of multiple facility expansions and technology upgrades, including the implementation of an internally engineered restricted access barrier system (RABS) concept for increased operational excellence in aseptic manufacturing. The RABS technology allows for faster start-up time, ease of changeover and reduced capital costs.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">As pharmaceutical companies ramp up investment in flexible in-house technologies and continue acquiring their own contract services providers, contract manufacturers are understanding the need to specialize — especially surrounding the growth of biologic drugs and biosimilars, including the growing demand for novel therapies. CMOs are increasing their investments in single-use technologies for biopharmaceutical manufacturing and continuous manufacturing processes.</span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Aware of their critical role in an increasingly sophisticated global supply chain, today’s contract manufacturers are innovating to provide high quality, flexible production.</span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;"><strong style="box-sizing: inherit;">INTEGRATING TECHNOLOGY</strong></span>Trends and advancements in the pharmaceutical industry tend to trigger cascading responses from linked industries, such as equipment, packaging and drug delivery devices. Take, for example, the continued focus on patience compliance and biologics, which has evolved into a growing market for combination products — the marriage of biological products, drug containers and drug delivery devices.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Drug manufacturers who have typically only dealt with making drugs have needed to broaden their in-house expertise or contract manufacturing reach to be able to address the technical, commercial and regulatory issues that have emerged with combination devices. </span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">According to Jessica Buday, senior manager, Process & Operational Excellence, <a href="http://www.ferringusa.com/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">Ferring Pharmaceuticals</a>, the pharmaceutical landscape today involves, “being prepared for not just the new products, but the new technology that is required (preferably in-house) to manufacture them. For instance, drug delivery now involves more than just tablets and vials — there is the entire world of combination devices. The companies that master development and validation of these devices will put themselves at the forefront. In manufacturing, that includes making sure we have the equipment for commercializing these devices.”</span></div>
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Ferring Pharmaceuticals, known for its reproductive health treatments, also focuses on offering more effective drug-delivery devices, including needle-free devices and transdermal delivery technologies. In March of last year, Ferring entered the U.S. pediatric endocrinology market with the acquisition of Zomacton growth hormone deficiency treatment and with it, the Zoma-Jet needle-free delivery device from Teva Pharmaceutical.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">For <a href="http://www.westpharma.com/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">West Pharmaceutical Services</a>, a company at the forefront of combination devices, successful drug therapy is a comprehensive strategy. “Our customers work hard to come up with innovative new molecules, but a drug molecule is completely useless unless delivered to patients in the best way,” says Graham Reynolds, vice president and general manager, Biologics, West Pharmaceutical Services. For West, there are four elements that need to be considered in successful drug therapy: the molecule itself, the container that holds it, the delivery system that administers it and the fourth — often forgotten element — patience adherence. “The interfaces between these elements are as critical as the phases themselves,” adds Reynolds. </span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">These “interfaces” are also driving equipment trends. For example, the increasingly important role that aseptic processing single-use systems play in the fill/finish process. Single-use components are helping manufacturers decrease time spent on cleaning and validation, thus saving them money. The newer, disposable technology enables fully integrated, continuous production.</span></div>
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It’s not so much the stand-alone technologies that drugmakers are reaching for, but rather, targeted innovation that enhances overall the effectiveness of the process. </div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;"><strong style="box-sizing: inherit;">PRECISION MEDICINE</strong></span>Precision medicine, as defined generally by the National Institutes of Health, is an “emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person.” While still in somewhat of a nascent stage, public interest has grown since last January when President Obama announced the Precision Medicine Initiative (PMI) in his State of the Union address.</div>
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As the pharmaceutical industry moves forward with its quest to innovate and streamline, this patient-centered, data-driven approach makes sense. Brad Campbell, president and COO of <a href="http://www.amicusrx.com/" style="background: transparent; box-sizing: inherit; color: #ccad68; text-decoration: none;" target="_blank">Amicus Therapeutics</a>, points to the rise of precision medicines as a real example of innovation. Precision medicine, according to Campbell, enables us to “drive science toward not just a specific disease but a specific genetic substrate. It helps improve the risk-benefit ratio, removing ‘waste’ from the system.” </div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Amicus is in the process of seeking global approvals for its lead product candidate, migalastat, a personalized medicine in late-stage development to treat individuals with Fabry disease. Fabry disease is a rare, inherited disorder caused by deficiency of an enzyme called α-galactosidase. In terms of Amicus’ work on its migalastat treatment, this precision medicine approach is designed for patients with “amenable mutations,” that is, specific mutations that are capable of responding to oral migalastat as a monotherapy treatment. Amicus’ extensive preclinical and clinical work has characterized the properties of nearly 800 known Fabry disease-associated mutations in an effort determine which patients are most eligible for treatment.</span></div>
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The result? “The use of elegant science to identify, with high precision, which patients will benefit,” states Campbell.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">In June 2015, the National Cancer Institute (NCI) announced a precision medicine trial touted as “the first study in oncology that incorporates all of the tenets of precision medicine.” The trial, called NCI-MATCH, seeks to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective, regardless of their cancer type. Obama’s PMI budget request included $70 million for NCI to scale up efforts to identify genomic drivers in cancer. The robust list of pharmaceutical partners involved in NCI-MATCH includes Novartis, Pfizer, Boehringer Ingelheim, AstraZeneca, as well as device manufacturer, Thermo Fisher Scientific.</span></div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;"><strong style="box-sizing: inherit;">NEXT-GENERATION DEMANDS</strong></span>Specifically speaking about precision medicine, Campbell stressed the industry’s need to “move away from the shotgun approach” to treatment, but perhaps this statement has wider implications for today’s pharmaceutical industry. The practice of cranking out rapid-fire innovation in the form of new molecules with the hopes of finding the next blockbuster is being replaced by targeted innovation strategies that demonstrate actual patient value and can be duplicated across an enterprise.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Today’s patients are more informed and connected with their health decisions than ever before. With that in mind, pharmaceutical manufacturers are making smarter choices when it comes to acquisitions, new technology and contract partners. Next-generation patients demand next-generation innovation, and the pharmaceutical industry is rising to the challenge. </span></div>
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<em style="box-sizing: inherit;"><span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">Editor’s note: Special thanks to our friends at Choose New Jersey and BioNJ for their assistance in the form of sharing their vast network of innovative contacts with us. Please visit them at</span></em></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-31312809107051787072016-10-18T11:21:00.001-07:002016-10-18T11:21:12.696-07:00Strategies for HVAC Systems<div class="articleparts" style="background-color: white; border: 0px; filter: none !important; font-family: Arial, verdana, helvetica, sans-serif; font-size: 16px; font-stretch: inherit; font-variant-numeric: inherit; line-height: 1.75em; margin-left: 297.766px; padding: 0px 0px 1em; vertical-align: baseline;">
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Heating and air-conditioning systems account for 50-80 percent of the total energy use in most commercial and institutional buildings. With such a high percentage of energy use concentrated in these two areas, it is no surprise that the recent rise in energy prices and concerns over energy supplier reliability have prompted maintenance and engineering managers to focus attention on these systems, particularly boilers and chillers.Even a slight improvement in the operating efficiency of these components translates into big cuts in energy use and costs. Suppose the average load on a large chiller plant is 3,000 tons. If a manager can improve its average operating efficiency from 0.91 kW/ton to 0.70 kW/ton, the monthly savings will top $27,000, assuming an average electricity cost of $0.06 per kWh.</div>
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While managers can take many steps to improve the operating efficiency of chillers and boilers, all energy-improvement programs should start by making existing equipment operate as efficiently as possible.</div>
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How can technicians achieve this goal? Two steps can enhance operation - monitoring and maintenance. Basic maintenance, such as cleaning and adjustments, will keep boilers and chillers operating so they minimize energy use.</div>
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But the only way to achieve peak operating efficiencies is to regularly monitor operating parameters. Data from a monitoring program will tell operators how to adjust the equipment and will identify the need for maintenance tasks.</div>
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Chiller Monitoring</h3>
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Chillers present a challenge to managers when it comes to operating efficiency. While manufacturers rate chiller efficiency at full load, most building chillers rarely operate at full load. Part-load efficiencies are lower and vary with a number of parameters, including supply and return chilled-water temperatures, entering condenser-water temperature, and condenser and chilled-water flow rates.</div>
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Compounding the challenge is the level of precision needed in measuring each parameter to calculate efficiency accurately. An error of as little as 1 degree in water-temperature measurements can cause an error in the efficiency calculation of 1-2 percent. A similar error in flow measurement can result in an even larger error in calculating efficiency. Therefore, it is critical to install high-quality flow meters and temperature sensors and to maintain them properly.</div>
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To be effective, a chiller efficiency-monitoring program must be ongoing. As data is collected under different operating conditions, managers will develop an efficiency performance baseline for the chiller. Technicians should compare this baseline to the manufacturer's published performance curve to determine if the chiller is performing as efficiently as possible.</div>
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As data continues to be compiled, technicians will be able to monitor trends in performance. While managers can expect a slight deterioration in performance, due to normal wear and tear, they should look for trends that might indicate a need for maintenance, such as cleaning the chiller's tubes, a replacing refrigerant, or overhauling the chiller.</div>
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Fortunately, a new generation of monitoring equipment is available to assist managers in monitoring chiller performance. This equipment collects the necessary data and automatically calculates the chiller's efficiency.</div>
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The equipment then compares the operating parameters and the calculated efficiency to past performance values, triggering an alarm if a value falls outside the expected range. By constantly monitoring chiller operation, the systems assist in keeping chillers at peak operating efficiency, and they help technicians detect and troubleshoot problems.</div>
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Boilers</h3>
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Efficiency calculations for chillers determine overall efficiency expressed as the ratio of energy input to energy output. Boilers require a different efficiency calculation - combustion efficiency.</div>
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A boiler's combustion efficiency measures how completely fuel burns and how effectively the generated heat transfers to water or steam. The measurement does not take into account heat loss from the boiler's surface, blowdown loss, or energy used by auxiliary equipment. With good test equipment, technicians can measure it with 98 percent accuracy or greater.</div>
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Managers have two reasons for using the combustion test instead of an overall efficiency test. First, it is practically impossible to measure all necessary parameters accurately, including the energy content of the fuel. More importantly, boiler losses excluded from the combustion efficiency calculation remain relatively constant. While technicians need to check them periodically, they do not require ongoing monitoring.</div>
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Combustion-efficiency testing is one of the most accurate means of adjusting a boiler and its auxiliary equipment for both safe and efficient operation. To do so, technicians can install a portable unit temporarily on a boiler for testing or permanently for ongoing monitoring.</div>
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Technicians most often use oxygen sensors to test a boiler's combustion efficiency. The equipment uses an electronic sensor in the boiler's flue that measures oxygen in the flue gas. Changes in combustion efficiency, such as those caused by varying levels of excess air, show up as varying levels of oxygen in the flue gas.</div>
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For small boilers, technicians most often use a portable combustion-efficiency tester setup at the beginning of every heating season. By adjusting the boiler each year, managers can achieve higher levels of operating efficiency in multiple small boilers without making a significant investment in equipment.</div>
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Medium-sized boilers can use the same setup, but technicians can achieve greater efficiency by testing the boiler at least monthly during the heating season. For larger boilers, it is most effective to permanently install the equipment and connect it to the boiler's control system. In this configuration, technicians can use the equipment to adjust the boiler under all heating loads to achieve the most efficient operation.</div>
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Pumps</h3>
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Managers often overlook pumps when looking for ways to improve HVAC system operating efficiency. As a result, inefficient pump operation can go uncorrected for the life of the system. And with most HVAC system pumps operating when the system operates, inefficiency can result in large amounts of lost energy.</div>
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Perhaps the most important factor when installing pumps is that specifiers must match them to the system's requirements. As the flow rate increases or decreases from the design point of the pump, the efficiency of the pump decreases. So it is important that managers select a pump based on the system's required flow rate and the pressure exerted on the pumping system. If the system must operate over a range of flow rates, a variable-speed pump system provides the best operating efficiency.</div>
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Once in operation, technicians should periodically test pumps for proper flow rate and pressure differential. And they should plot readings against the manufacturer's pump curve to determine if the pump is operating within its specified range.</div>
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<em style="border: 0px; filter: none !important; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">James Piper, P.E., is a national consultant based in Bowie, Md., with more than 25 years of experience in facilities maintenance and engineering issues.</em></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-21525940148512887552016-10-18T11:20:00.000-07:002016-10-18T11:20:19.212-07:005 Steps to Chiller Efficiency<div style="background-color: white; border: 0px; filter: none !important; font-family: Arial, verdana, helvetica, sans-serif; font-size: 16px; font-stretch: inherit; font-variant-numeric: inherit; line-height: 1.75em; margin-bottom: 1em; margin-left: 297.766px; margin-top: 1em; padding: 0px 0px 1em; vertical-align: baseline;">
Chillers represent a substantial capital investment and are a major contributor to operating costs in institutional and commercial facilities. For many organizations, chillers are the largest single energy users, and comprehensive maintenance is critical to ensure their reliability and efficient operation.</div>
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While some organizations use predictive maintenance — including vibration analysis, infrared thermography, and rotor bar testing — to diagnose problems in advance, a comprehensive preventive maintenance (PM) plan remains the key to ensuring the best performance and efficiency of a chiller.</div>
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Chiller efficiencies have improved steadily over the past decade due to advances in controls, refrigerants and equipment design. As a result, chillers now have tighter operational tolerances, and regular service and maintenance are more crucial than ever. When developing a PM plan for chilling equipment, maintenance and engineering managers should consider five essential areas.</div>
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Step 1: Maintain a Daily Operating Log</h3>
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Chiller operators should document chiller performance daily with an accurate and detailed log, comparing this performance with design and start-up data to detect problems or inefficient control setpoints. This process allows the operator to assemble a history of operating conditions, which can be reviewed and analyzed to determine trends and provide advanced warning of potential problems.</div>
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For example, if machine operators notice a gradual increase in condensing pressure during a month’s time, they can consult the daily operating log and systematically check and correct the possible cause of this condition, such as fouled condenser tubes or non-condensables.</div>
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Chiller manufacturers can provide a list of recommended data points specific to equipment upon request. Operators can take data readings daily, once per shift at about the same time. Today’s chillers are controlled via microprocessor controls, so managers can automate this process using microprocessor-controlled building automation systems.</div>
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Step 2: Keep Tubes Clean</h3>
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One large potential hindrance to desired chiller performance is heat-transfer efficiency. Chiller performance and efficiency relate directly to its ability to transfer heat, which begins with clean evaporator and condenser tubes. Large chillers contain several miles of tubing in their heat exchangers, so keeping these large surfaces clean is essential for maintaining high-efficiency performance.</div>
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Chiller efficiency deteriorates as tubes become fouled, when mud, algae, sludge, scale or contaminants accumulate on the waterside of heat-transfer surfaces. The rate of fouling depends on the system type — open or closed — as well as on water quality, cleanliness and temperature.</div>
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Most chiller manufacturers recommend cleaning condenser tubes annually, since they typically are part of an open system, and they recommend cleaning evaporator tubes once every three years for closed systems. But if the evaporator is part of an open system, they recommend periodic inspection and cleaning.</div>
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Managers can consider two primary methods for cleaning tubes:</div>
<ul style="background-color: white; border: 0px; filter: none !important; font-family: Arial, verdana, helvetica, sans-serif; font-size: 16px; font-stretch: inherit; font-variant-numeric: inherit; line-height: 1.75em; list-style: none; margin: 1em 0px 1em 297.766px; padding: 0px 0px 0px 25px; vertical-align: baseline;">
<li style="border: 0px; filter: none !important; font-family: inherit; font-size: 15px; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; padding: 5px 0px 0px; vertical-align: baseline;">Mechanical cleaning removes mud, algae, sludge and loose materials from smooth-bore tubes and consists of removing the water-box covers, brushing the tubes and flushing with clean water. For internally enhanced tubes, managers should consult the chiller manufacturer for mechanical-cleaning recommendations.</li>
<li style="border: 0px; filter: none !important; font-family: inherit; font-size: 15px; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; padding: 5px 0px 0px; vertical-align: baseline;">Chemical cleaning removes scale. Most chiller manufacturers recommend consulting with a local water-treatment supplier to determine the proper chemical solution required. A thorough mechanical cleaning should always follow a chemical cleaning.</li>
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New chillers feature automatic tube-brushing systems, which can be retrofit onto existing chillers. These systems use small, nylon-bristled brushes that flow through the tubes for cleaning. A custom-manufactured, four-way reversing valve is installed in condenser water-piping system, and every six hours, the system automatically reverses the flow through the condenser tubes for about 30 seconds.<br style="border: 0px; margin: 0px; padding: 0px;" />Coupled with proper water treatment, these systems virtually eliminate fouling within the chiller and maintain design-approach temperatures. These systems typically show payback periods of less than two years.</div>
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Step 3: Ensure a Leak-free Unit</h3>
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Manufacturers recommend quarterly tests of compressors for leaks. Low-pressure chillers using either CFC-11, which has been phased out, or HCFC-123 have sections of their refrigeration systems that operate at subatmospheric pressure. Although these chillers are the most common in today’s facilities, it is difficult to create a perfectly sealed machine, and leaks allow air and moisture, commonly referred to as non-condensables, to enter the unit.</div>
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Once in the chiller, non-condensables become trapped in the condenser, increasing condensing pressure and compressor-power requirements and reducing efficiency and overall cooling capacity. Low-pressure chillers have high-efficiency purge units that remove non-condensables to maintain design-condensing pressure and promote efficient operation. One chiller manufacturer estimates that 1 psi of air in a condenser equates to a 3 percent loss in chiller efficiency.</div>
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Moisture in a chiller also can create acids that corrode motor windings and bearings and create rust inside the shell. Small rust particles called fines float in the vessels and get trapped inside heat-exchanger tubes. Fines on tubes decrease the unit’s heat-transfer effectiveness and overall efficiency. Left unchecked, they can lead to costly tube repairs.</div>
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The best way to monitor leaks in a low-pressure chiller is to track purge-unit runtime and the amount of moisture accumulation at the purge unit. If either of these figures is too high, the unit has leaks. Other indications of air in the system include increased head pressure and condensing temperature.</div>
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High-pressure chillers using CFC-12, HFC-134a, or HCFC-22 operate at pressures well above atmospheric pressure, and leaks in these types of chillers release potentially hazardous refrigerants into the environment. Environmental regulations limit the amount of annual refrigerant leaks.</div>
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Leaks also results in a lower refrigerant charge and other operational problems, such as lower evaporator pressure, which can cause the compressor to work harder to produce a lower cooling capacity. For positive-pressure chillers, technicians should monitor the refrigerant charge level and evaporator pressure to detect leaks.</div>
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Step 4: Sustain Proper Water Treatment</h3>
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Most chillers use water for heat transfer, so the water must be properly treated to prevent scale, corrosion and biological growth. A one-time chemical treatment is required for closed-water systems, which are typical of chilled-water systems connected to the chiller evaporator.</div>
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Open systems typically are used for condenser-water systems connected to the chiller condenser. Condenser systems that use sources such as cooling towers require continuous chemical water treatment. Managers should work with a chemical-treatment vendor familiar with local water supplies and can provide full-service maintenance for all facility water systems.</div>
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Scale should not be a problem if the vendor maintains proper chemical treatment of the evaporator and condenser-water systems. The presence of scale in the condenser or evaporator tubes indicates improperly treated water. The vendor needs to test water quality every three months and correct the water treatment program, which should aid in cleaning the chiller tubes.</div>
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Also, all systems strainers should be cleaned every three months. Sand filters and side-stream filters for condenser-water systems are very effective at maintaining clean water, if properly maintained. To determine when cleaning is required, technicians should monitor pressure drop at the filters and refer to manufacturer recommendations on cleaning. Filters should be cleaned quarterly, regardless of pressure drop.</div>
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Maintenance of strainers and filters limits chiller-tube erosion caused by sand or other small particles moving at high velocities. Erosion and tube pitting decreases overall heat-transfer effectiveness and decreases efficiency. If uncorrected, these conditions can lead to plugged tubes or catastrophic tube failure.</div>
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Technicians should inspect chilled-water and condenser-water piping systems annually for evidence of corrosion and erosion. Most manufacturers recommend eddy-current inspection of heat-exchanger tubes, including an electromagnetic procedure for evaluating tube-wall thickness, every three-five years.</div>
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Step 5: Analyze Oil and Refrigerant</h3>
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Annual chemical analysis of oil and refrigerant can aid in detect chiller-contamination problems before they become serious. Testing consists of spectrometric chemical analysis to determine contaminants, including moisture, acids and metals, which hamper performance and efficiency. A qualified chemical laboratory specializing in HVAC equipment must perform the analysis. Most manufacturers provide annual oil and refrigerant analysis services.</div>
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Technicians should take an oil sample while the chiller is operating. The oil should be changed only if indicated by oil analysis. Technicians also should monitor oil filters for pressure drop and change them during a recommended oil change or if pressure drop is outside of tolerance.</div>
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Oil analysis can help detect other chiller problems. For example, high moisture content in the oil can signal problems with the purge unit, and changes in oil characteristics can signal the development of unacceptable compressor wear.</div>
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Managers use refrigerant testing to determine contaminants that might lead to reliability and efficiency problems. One main contaminant is oil that migrates into the refrigerant. One chiller manufacturer estimates there is a 2 percent loss in chiller efficiency for every 1 percent oil found in the refrigerant, and it is not uncommon to find 10 percent oil in older chillers’ refrigerant. Based on this estimate, such contamination can lead to a substantial 20 percent decrease in efficiency. The bottom line — testing can pay large dividends.</div>
<div style="background-color: white; border: 0px; filter: none !important; font-family: Arial, verdana, helvetica, sans-serif; font-size: 16px; font-stretch: inherit; font-variant-numeric: inherit; line-height: 1.75em; margin-bottom: 1em; margin-left: 297.766px; margin-top: 1em; padding: 0px 0px 1em; vertical-align: baseline;">
<em style="border: 0px; filter: none !important; font-family: inherit; font-size: inherit; font-stretch: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Kevin M. Graham, P.E., is a project manager with 10 years’ experience for <a href="http://www.ssr-inc.com/" style="border: 0px; color: #666666; filter: none !important; font-family: inherit; font-size: inherit; font-stretch: inherit; font-style: inherit; font-variant: inherit; font-weight: inherit; line-height: inherit; margin: 0px; padding: 0px; vertical-align: baseline;" target="_ms">Smith Seckman Reid Inc.</a> an engineering and facility consulting firm.</em></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-69073719459069180822016-10-18T11:14:00.001-07:002016-10-18T11:14:57.773-07:00THE CONTROL ENVIRONMENT OF A COMPANY<div style="background: rgb(255, 255, 255); color: #333333; font-family: Helvetica, Arial, sans-serif; font-size: 1.2em; line-height: 1.4; margin-bottom: 10px; padding: 0px; vertical-align: baseline;">
<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">The purpose of this article is to provide candidates with a more detailed appreciation of matters pertinent to an auditor, focusing on the need for the auditor of a large limited liability company (in the UK – a limited company) to evaluate the effectiveness of the company’s control environment</strong></div>
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ISA 315, <em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Identifying and Assessing the Risks of Material Misstatement through Understanding the Entity and Its Environment</em>,<em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;"> </em>sets out the auditor’s responsibility to identify and assess the risks of material misstatement in the financial statements, through understanding the entity and its environment including the entity’s internal control. One of the five components of internal control is the control environment and it is recognised that the control environment within small entities is likely to differ from larger entities. Many candidates have not yet had the opportunity of working in larger entities, or have chosen not to, so have not been exposed to working within the type of strong control environment often referred to in auditing texts. Consequently, they often have limited experience on which to draw when answering exam questions that require anything other than superficial knowledge of an entity’s control environment.</div>
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This article aims to provide common examples of matters the auditor needs to consider when assessing an entity’s control environment, and in making an assessment as to their impact on the risk of material misstatement in the financial statements. Reflecting the general trend of exam questions testing knowledge of this area, the article focuses on the need for the auditor of a large limited liability company (in the UK – a limited company) to evaluate the effectiveness of the company’s control environment.</div>
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A company’s control environment comprises seven elements each requiring careful consideration by the company’s auditor, recognising that some elements may be more pertinent than others – depending on the subject company. Each one of these elements is identified below, along with an explanation of specific practical aspects that may be considered by the auditor when evaluating its effectiveness. Candidates should be aware that this process forms part of the auditor’s assessment of the overall effectiveness of the company’s internal control, relevant to the audit.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">1 Communication and enforcement of integrity and ethical values</strong><br />Many companies have high values and seek to promote honesty and integrity among their employees on a day-to-day basis. Clearly, if it is evident that such values do exist and are communicated effectively to employees and enforced, this will have the effect of increasing confidence in the design, administration and monitoring of controls – leading to a reduced risk of material misstatement in a company’s financial statements. For example, where a company adopts comprehensive anti-bribery and corruption policies and procedures with regard to contract tendering, and has formal employee notification and checking practices in this regard, it follows that there is reduced risk of material misstatement due to the omission of provisions for fines for the non-compliance with relevant laws and regulations. Alternatively, the existence in a company of comprehensive and ethical procedures with regard to the granting of credit facilities to customers and the pursuance of payment of for goods and services supplied, together with regular supervisory control in this respect, is likely to lead to increased audit confidence in the trade receivables area. This is because the existence of a system allowing goods and services to be a supplied on credit to customers provides the opportunity for fraud to be perpetrated against the company by employees and customers, particularly if controls are deficient in terms of their design or implementation.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">2 Commitment to competence</strong><br />Competence is the knowledge and skills necessary to accomplish tasks that define the individual’s job. It is self-evident that if individual employees are tasked with carrying out duties that are beyond their competence levels, then desired objectives are unlikely to be met. For example, there is an increased probability that the objective of avoiding material misstatement in a set of complex financial statements will not be met if prepared by an inexperienced company accountant. This is simply due to the inexperience (translating to a lower competence level) of the accountant. From this, it follows that the auditor will have increased confidence in internal control relevant to the audit, where management have taken measures to ensure employees who participate in internal control are competent to carry out relevant tasks effectively. Measures taken by management in this regard can cover a range of activity including for example, rigorous technical and aptitude testing at the employee recruitment stage and in-house or external training courses and mentoring from more senior colleagues</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">3 Participation by those charged with governance</strong><br />The directors of a limited liability/limited company are charged with the company’s governance. As such, they are responsible for overseeing the strategic direction of the company and its obligations related to its accountability – for example, to governments, shareholders and to society in general. In particular, in most jurisdictions the company’s directors are responsible for the preparation of its financial statements. Given the influence that the actions of directors have on a company’s internal control, the extent of their day-to-day active involvement in the company’s operations has a pervasive effect on the internal control of the company.</div>
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The extent to which directors do get involved will, to some extent, depend on legislation or codes of practice setting out guidance for best practice in given jurisdictions. For example, the UK Corporate Governance Code (with which companies listed on the London Stock Exchange should comply) sets out standards of good practice, including those pertaining to board leadership and effectiveness. Notwithstanding legislation and codes of practice, the extent of each director’s participation is largely influenced by the nature of their professional discipline and their individual perspective about how they should carry out their respective roles. Some may see themselves as micromanagers, while others will trust subordinates to carry out defined duties with minimal interference. Frequently, directors will be very experienced and adopt an arms-length approach to getting involved in operational tasks. However, they may insist on monitoring activity by way of receipt of formal narrative reports. Other directors may adopt a more casual (but equally thorough!) ‘working alongside subordinates’ approach as a method of monitoring activities.</div>
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All of the variables mentioned above with regard to director involvement, should be important considerations of an auditor as part of the process of ascertaining the extent of internal control in the company and in assessing its effectiveness.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">4 Management’s philosophy and operating style</strong><br />A company’s board of directors will comprise of individuals each with a different mind – set as to philosophy and operating style, manifested in characteristics such as their:</div>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">approach to taking and managing business risk</li>
<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">attitudes and actions toward financial reporting</li>
<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">attitudes toward information processing and accounting and functions personnel.</li>
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<br />Each of the above characteristics underlie a company’s control environment and it is crucial for an auditor to have an understanding of them. Dealing with each in turn:</div>
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<em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Approach to taking and managing business risk.</em> Business risk is the risk inherent in a company as a consequence of its day-to-day operations and it comprises several components. The first of these is financial risk – for example, the risk that the company may have insufficient cash flow to continue in operation. The second component is operational risk – for example, the risk that the company’s product lines may decline in popularity leading to a sharp decline in sales and profitability. The final component of business risk is compliance risk – for example, the risk that the company may be in breach of health and safety regulations, leading to the possibility of hefty fines or even the closedown of operational activity.</div>
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Candidates should be aware that a risk-based approach to an audit requires the identification and assessment of inherent risk factors and then of the control risk pertaining to these, in order to determine the risk of material misstatement, prior to carrying out substantive procedures. By adopting a top-down approach to the audit and first identifying business risks, auditors should be able to identify the associated inherent risks arising. They can then progress through the audit using the audit risk model (audit risk = the risk of material misstatement x detection risk) to determine the amount of detailed testing required in each area of the financial statements. To illustrate this approach, referring to the compliance risk example above, an inherent risk arising from the risk of a breach of health and safety regulations. As a consequence, there is a risk that the company’s liabilities may be understated due to the omission of a provision required in the financial statements, in respect of a fine for a non-compliance.</div>
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The directors’ approach to taking and managing business risk has obvious ramifications on a company’s financial statements, and the auditor should be aware of the various factors that influence directors in this area, and of applicable controls in place. It is often the case that a newly established company with young entrepreneurial directors and a flat management structure will have a more liberal approach to taking and managing business risk than a well-established company with more experienced directors, and a steep hierarchical management structure. Consequently, it is likely that there would be a lower level of a risk of material misstatement in the financial statements of the latter company.</div>
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<em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Attitude and actions toward financial reporting. </em>Financial Reporting Standards exist to help facilitate fairness, consistency and transparency of financial reporting. However, some determinants of profitability such as the measure of depreciation, the valuation of inventory or the amount of a provision remain open to the subjective judgment of management. Consequently, the auditor needs to gain an understanding of directors’ attitudes and actions to financial reporting issues and then make a judgment as to the extent of reliance that can be placed upon these. It may be that a company that is struggling in a faltering economy, and in another driven by a culture to report increasing profits, there is a tendency to adopt aggressive (as opposed to conservative) accounting principles, in order to meet profit expectations. Clearly, on such audit engagements it is important for the auditor to remain resolute in exercising appropriate levels of professional scepticism throughout.</div>
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<em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Attitude towards information processing and accounting functions and personnel.</em><u style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;"></u>Properly financed and resourced with sufficient numbers of appropriately qualified staff and contemporary information and communications technology, the financial reporting (accounting) and information processing functions of a company are vital to a company’s ongoing existence. They are key to the facilitation of compliance with laws and regulations, transactions with third parties, administration and control systems and in the provision of information for decision making. In most very large companies many aspects of the accounting function are inextricably intertwined with specific aspects of the company’s information processing systems, and there is an ongoing programme of investment in these, to ensure that the accounting and information processing systems are contemporary and fit for purpose. This is reflective of a situation where directors recognise that business risk will be significantly reduced, if the company has effective information processing and accounting functions. However, this situation does not apply to all companies. In some, both functions may be seen by the directors merely as necessary functional overhead areas of the business and, as such, they become under-funded and inadequately resourced in terms of staffing and equipment. An auditor engaged on an audit in such a company should be aware that there is an increased risk of material misstatement in the financial statements.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">5 Organisational structure</strong>ISA 315 describes a company’s organisational structure as being ‘the framework within which an entity’s activities for achieving its objectives are planned, executed, controlled and reviewed’. The appendix to the ISA then explains ‘that the appropriateness of an entity’s organisational structure depends, in part, on its size and the nature of its activities’. It follows from this that an international consulting company with offices and operations in several countries has different priorities in terms of organisational structure to a national car sales company with several offices and a number of sales branches in a single country. Similarly, the organisational structure deemed suitable for such a car sales company would not be appropriate for a single site manufacturing company. Generally, an auditor may reasonably expect there to be a positive correlation between the level of inherent risk and the size and complexity of a company’s operations. In assessing, the level of the risk of material misstatement the auditor should consider as to whether the company’s organisational structure in terms of authority, responsibility and lines of reporting meet desired objectives.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">6 Assignment of authority and responsibility<em style="background: transparent; margin: 0px; padding: 0px; vertical-align: baseline;"><br /></em></strong><em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Normally, the </em>larger a company’s scale of operations, then the larger the size of the workforce and, inevitably, the larger the amount of assignment of authority and responsibility that is required. Consequently, companies need to deal not only with ensuring that appropriate levels of authority and responsibility are assigned to appropriately qualified and experienced individuals. They also need to ensure that adequate reporting relationships and authorisation hierarchies are in place. Additionally, individuals need to be properly resourced and made fully aware of their responsibilities and of how their actions interrelate with the actions of others and contribute to the objectives of the company. If a company is not successful in meeting each of these needs, then there is an increased probability of ineffective decisions, errors and oversights by employees leading to an increased risk of material misstatement in its financial statements. For example, where a wages clerk is authorised to process the wages payroll and is then assigned the (inappropriate!) authority to enter new employee details into the wages master file.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">7 Human resources policies and practices</strong><em style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;"><br /></em>As explained in ISA 315, ‘human resource policies and practices demonstrate important matters in relation to the control consciousness of an entity’. This implies that if human resources policies and practices are considered to be sound both in design and in implementation over a range of matters, then the risk of material misstatement will be reduced.</div>
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Examples of these matters include:</div>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">Recruitment policies and procedures. These should ensure that only competent individuals with integrity are employed by the company. Interview procedures should ensure that only candidates meeting the company’s criteria for recruitment are engaged.</li>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">There should be adequate induction procedures for new employees, such that they can carry out their assigned responsibilities effectively and efficiently soon after being engaged by the company.</li>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">Employees should be provided with ongoing training, support and mentoring as appropriate, such that they can continue to carry out their assigned responsibilities effectively and efficiently.</li>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">There should be regular formal appraisal, at least annually of an employee’s performance. Performance should be measured against standardised criteria authorised by senior management of the company, and there should be ongoing monitoring and feedback to employees about their performance and development needs.</li>
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<ul style="background: rgb(255, 255, 255); color: #333333; font-family: Helvetica, Arial, sans-serif; font-size: 10px; list-style: none; margin: 0px 0px 1em; padding: 0px; vertical-align: baseline;">
<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">The company should employ comprehensive and transparent employment grievance procedures, such that employees can be confident that grievances will be dealt with openly and impartially.</li>
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<ul style="background: rgb(255, 255, 255); color: #333333; font-family: Helvetica, Arial, sans-serif; font-size: 10px; list-style: none; margin: 0px 0px 1em; padding: 0px; vertical-align: baseline;">
<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">There should be open, transparent and equitable employee disciplinary procedures, such that employees can be confident they will not be treated unfairly by the company in the event that an action triggers its disciplinary process.</li>
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<li style="background: transparent; font-size: 12px; list-style-image: url("../img/bullet.png"); list-style-position: outside; margin: 0px 0px 0.25em 30px; padding: 0px; vertical-align: baseline;">Employment termination procedures should incorporate provision for an exit interview so that the reason for the termination can be confirmed or clarified, all emoluments due to the employee can be settled and arrangements can be made for the return of all company assets prior to the termination date.</li>
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While each of the above measures will have a positive impact on the internal control of a company, to some extent they all have the effect of reducing the risk of material misstatement in the financial statements. For example, the existence of fair and robust grievance and disciplinary procedures reduce the possibility of a successful claim against the company for constructive or unfair dismissal, and the absence of a material provision in this respect. Significantly, the existence of human resources policies and practices that are the same or similar to those above should leave a favourable impression with the auditor, as to the directors’ attitude toward their company’s workforce. It is likely that such an attitude would foster good working relationships with employees, leading to an increased likelihood that individuals would reciprocate by carrying out their tasks diligently with integrity in the best interests of the company – resulting in a reduced risk of material misstatement.</div>
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<strong style="background: transparent; font-size: 12px; margin: 0px; padding: 0px; vertical-align: baseline;">Summary</strong><br />As indicated at the beginning of this article, the purpose of it is to provide candidates with a more detailed appreciation of matters pertinent to an auditor, when evaluating the control environment of a limited liability/limited company. When asked to explain what is meant by the term ‘control environment’, they typically comment that it is a component of a company’s internal control and that it centres around how a company is operated by its management, reflecting such matters as their philosophy and operating style. While there is some merit in this answer, having now read the above commentary, candidates should be aware that the term has much more meaning than that.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-39525670025175485832016-10-16T12:44:00.004-07:002016-10-16T12:44:56.530-07:00Innovation in Quality Metrics<div style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25;">
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The FDA is collaborating with industry to develop a groundbreaking new set of state-of-quality metrics</h2>
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By Dr. Prabir Basu, Pharma Manufacturing, OPEX and cGMP Consultant; Dr. Nuala Calnan, Pharmaceutical Science & Regulatory Team at DIT, Ireland; Dr. Thomas Friedli, Professor, Institute of Technology Management, University of St.Gallen, Switzerland</div>
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Aug 16, 2016</div>
In the world of pharmaceutical production, it is universally understood that a robust pharmaceutical quality system provides key elements of assurance and oversight for pharmaceutical manufacturing processes. It ensures that patients are provided with medications that are safe, effective, and reliably produced at a high level of quality. However, despite recent advances in the manufacturing sector, quality issues remain a frequent occurrence, and can result in recalls, withdrawals, or harm to patients. Quality issues have also been linked to the rise in critical drug shortages.¹</div>
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Regulatory agencies currently assesses the risk profile of manufacturing sites based primarily on their compliance history, as seen in warning letters and field reports, in conjunction with records on product recalls and market-based quality problems. These are not necessarily the most informative measures, and by their nature, provide historical or lagging data or signal detection. More relevant data relating to the state-of-quality, provided in advance, would better inform the risk factors that might predict quality problems and future drug shortages.</div>
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FDA’s approach to quality oversight has evolved in recent years, and the new Office of Pharmaceutical Quality (OPQ) has made it a priority to establish a sounder basis for ensuring that pharmaceutical products meet high quality standards throughout the product lifecycle</div>
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This FDA led Research Project initiates a program aimed at developing and implementing a set of standardized manufacturing quality metrics. The establishment and collection of these metrics should provide various stakeholders – from industry to regulators – with greater insight into the state-of-quality at a given manufacturing facility, and allow stakeholders to better anticipate and address quality issues while simultaneously reducing unnecessary regulatory burden.</div>
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<strong style="box-sizing: inherit;">RECENT DEVELOPMENTS IN THE QUALITY METRICS INITIATIVE</strong>Since early 2013, FDA has been working with the pharmaceutical industry to develop goals and objectives for a metrics program. In response, several industry stakeholder groups have worked with FDA to develop consensus around the goals, as well as identify potential metric sets, including developing recommendations for their implementation and interpretation. Through a series of extensive engagements between industry and FDA there has been an acknowledgement of the complexity of the problem at hand, which is to develop a recommeded set of metrics which are objective and meaningful, easy to capture yet normalized to account for factors such as process differences and technical complexity. Furthermore, it is required that those elements selected will promote acceptable behaviors and not lead to any unintended consquences or unwanted behaviors.</div>
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<em style="box-sizing: inherit;">Key Research Questions to Address in the Selection of a Proposed Metrics Set:</em><br />
1. What is the appropriate set of metrics to collect for establishing the state-of-quality at a manufacturing facility?<br />
2. Will this set of metrics provide adequate information for all types of pharmaceutical manufacturing, such as sterile injectables, bio-pharmaceuticals?<br />
3. How should these metrics be defined?<br />
4. What is the optimal reporting process and what support will be necessary to facilitate timely and uniform reporting.<br />
5. What are the potential unintended consequences which may arise with chosen metrics?<br />
a. Such as measuring OOS rate may result in companies not reporting OOS results or changing their standards of identifying OOS results to minimize the numbers.<br />
b. Review of complaint trending might lead firms to resolve problems superficially without getting to root cause.<br />
6. How can the FDA prevent manipulation of data and its unintended consequences?<br />
7. How does company culture impact the data collection and the metrics?<br />
8. How does the underlying quality culture of a manufacturing facility influence quality performance and how does one correlate its impact through these metrics?<br />
9. How can one represent a set of complex behavior and performance criteria via a set of simple metrics?<br />
10. How can these set of metrics be linked to operating efficiency and performance of the plants? Plants are naturally focused towards improving their profitability and cost. Significant efforts such as six sigma, lean, right-first-time programs are underway across the industry and have deep rooted support in many pharmaceutical operations around the world. Can the reportable quality metrics be a natural offshoot of such improvement programs?</div>
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<strong style="box-sizing: inherit;">ROLE OF QUALITY METRICS IN RISK-BASED SURVEILLANCE</strong><br />
Quality metrics are widely used throughout the pharmaceutical industry to monitor quality control systems and processes, and many of the components that inform those metrics (e.g., data on process capability output or statistical process control) are already collected and maintained as part of cGMP compliance. Several measures of performance are already common throughout the industry. The challenege is that they are currently defined differently across manufacturers, and even between sites operated by the same manufacturer.</div>
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The proposed FDA Quality Metrics program is not the first of its kind; rather, it draws from the example of existing private sector quality improvement programs that collect voluntarily reported, standardized quality metrics from a large and varying array of manufacturing sites, which are then used by participating manufacturers to benchmark their performance against industry standards and their peers.</div>
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The collection and analysis of standardized quality metrics can serve several functions:<br />
• At a basic level, metrics should provide a quantitative and objective measure of quality at the manufacturing site, and provide a window at a systems level, to the effectiveness of the oversight and control of operations at a given site.<br />
• Metrics data collection and analysis should also help mitigate or reduce quality related drug shortages and recalls, by allowing for early identification of products at risk of quality failures.<br />
• Metrics provide an opportunity to stratify manufacturing sites according to quality risk and thus prioritize scarce regulatory resources for inspection of plants world-wide.<br />
• Ultimately, these metrics should assist pharmaceutical manufacturers to promote positive behaviors and a corporate culture of responsibility for quality, by providing incentives to improve product and process capability.<br />
Thus, quality metrics may contribute to ongoing broader FDA efforts to reducing risk and improving drug quality.</div>
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<strong style="box-sizing: inherit;">FDA OPQ OPEX RESEARCH GRANT</strong><br />
The University of St. Gallen is the academic leader today in this effort to establish solid and meaningful OPEX programs around the world. For more than a decade, it has been working hand-in-hand with the pharmaceutical industry globally to assist in developing widely accepted pharmaceutical manufacturing improvement programs. In July, the FDA OPQ granted University of St.Gallen, Switzerland a $468,641 grant to evaluate, enlarge and test the FDA quality metric based on the St.Gallen Operational Excellence database.</div>
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St.Gallen will collaborate on this project with Dublin Institute of Technology, Ireland and with Prabir Basu, Consultant and the former Executive Director of the National Institute for Pharmaceutical Technology and Education (NIPTE) in the U.S.A</div>
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This St. Gallen research project aims to identify an appropriate set of quality metrics that is integrated with the operation of a manufacturing facility and its underlying quality culture. Over the past 10-15 years the pharmaceutical industry has becoming increasingly aware of and embraced the benefits provided by formal OPEX programs. The initial driving forces behind these OPEX programs were the improvements in operational efficiency and potential cost savings which are often an essential component in the survival for these manufacturing facilities within the competitive global environment. Recent developments in the more mature OPEX programs have shown considerable benefits in the reduction of variation and comensurate improvements in quality through targeting measurable stabilization of the organisational systems responsible for equipment and facilities, quality management, inventory control and mangement oversight.</div>
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The significance of the proposed research project is that it will use operational data already available from nearly 300 global plants to establish the metrics, evaluate and validate them. Specifically, since there is extensive buy-in from within the pharmaceutical industry to the existing St. Gallen OPEX program and the benefits from participating in an international benchmarking process, it is believed that industry buy-in for the proposed quality metrics should be easier to achieve. Based on our extensive experience the metrics proposed by the St. Gallen team will also incorporate underlying factors impacting corporate culture such as management commitment and employee empowerment. It is imperative that these underlying factors become an integral part of any meaningful metrics system.</div>
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<strong style="box-sizing: inherit;">INNOVATION IN QUALITY METRICS</strong>This project builds on a 12 year experience of benchmarking research in the area of pharmaceutical production and management. This database is the one of its kind in the world and is unique in the sense that the data is already widely used by a large number of industry members across the world. The University of St. Gallen has been working together with leading pharmaceutical companies and has great practical and theoretical insights relating to both the current and future challenges in performance measurement for pharmaceutical production.</div>
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The evaluation of the proposed metric set will exclusively draw upon the University of St.Gallen OPEX database (no additional data collecting is foreseen). The St.Gallen Global OPEX Database currently consists of more than 300 data sets of pharmaceutical manufacturing sites from plants all over the world, but mainly of US and European based companies. Fig. 1 gives an overview the configuration of the current database: </div>
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<img alt="Fig. 1: Overview of the St.Gallen OPEX database" class="leftAlone" height="341" src="https://www.pharmamanufacturing.com/assets/Media/2016/1608/_resampled/ResizedImage599341-Fig1.png" style="border: 0px; box-sizing: inherit; clear: both; display: block; float: none; margin: 0px; padding: 0px;" title="" width="599" /><br />
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Fig. 1: Overview of the St.Gallen OPEX database</div>
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The database includes specific measures of both quantitative KPIs and qualitative Enablers of quality. It combines data from across the technical and social sub-systems within pharmaceutical organizations based on the innovative St.Gallen OPEX model shown in Fig 2. </div>
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<img alt="Fig. 2: The St. Gallen Operational Excellence Model" class="leftAlone" height="336" src="https://www.pharmamanufacturing.com/assets/Media/2016/1608/_resampled/ResizedImage600336-Fig2.png" style="border: 0px; box-sizing: inherit; clear: both; display: block; float: none; margin: 0px; padding: 0px;" title="St. Gallen Operational Excellence Model" width="600" /><br />
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Fig. 2: The St. Gallen Operational Excellence Model</div>
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The technical systems of the St. Gallen OPEX model consists of the elements of:<br />
• Total Productive Maintenance (TPM)<br />
• Total Quality Mangement (TQM)<br />
• Just in Time (JIT)</div>
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The first technical system, TPM, consists of measures that are related to the stability of the equipment within a pharmaceutical production facility. Secondly, the TQM measures consider KPIs and Enablers related to the stability of the relevant quality management processes. Lastly, JIT deals with production flow, related inventory levels and lead times. Available data has consistently shown a positive impact of TPM on TQM, and of both TPM and TQM on JIT. Production sites that have a high TPM performance and a high TQM performance have also demonstrated a high JIT performance.</div>
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The Social Sub-system of the model addresses a number of management, leadership and continuous improvement elements at a KPI and Enabler level. The benefits of using the formal St. Gallen OPEX model is that it provides opportunities to structure the discussion around quality and operational excellence from a system perspective. This is the fundamental basis for the St. Gallen OPEX database and benchmarking study.</div>
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This research proposal aims to relate, adapt and improve the existing OPEX research of the University of St. Gallen to the current needs of the FDA’s quality metrics initiative. The research team will investigate wide known excellence frameworks to detail the evaluations on the basis of existing data. Furthermore, it will use established data analysis methods and tools to show significant impacts and correlations between the underlying qualitative Enablers and the related quantitative KPIs in order to identify patterns and trends. The overall goal of the research team is to keep a system perspective of the entire company environment to capture as many influencing factors as possible and not neglect others. The evaluation will allow for exploring and understanding the interdependencies between Enablers and KPIs from this system perspective.</div>
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The outcome of this project will be a verified and proven set of quality metrics. Correlations will not only be tested against traditional quality performance figures like customer complaints or rejected batches but also against overall facility performance and cost figures. Furthermore, the Enablers for quality will be defined based on an overall system understanding taking into account key supply chain elements of supplier quality and distribution performance. Furthermore, the St.Gallen research team adresses the aspect of Quality Culture with the requested improvement culture of the employees.</div>
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<span style="box-sizing: inherit; font-size: 1.4rem; line-height: 1.25;">The next generation quality metrics program should support the aim of achieving enhanced product quality without the need for extensive regulatory oversight and should ultimately help to drive responsibilities for the manufacturers that will lead to a reduction in product-related shortages and quality related recalls. The developed concepts and methods will significantly support the further evaluation and use of the quality metrics to have an influence and positive impact on the industry peers.</span><strong style="box-sizing: inherit;"> </strong></div>
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<strong style="box-sizing: inherit;">1. ISPE. (2013). Report on the ISPE Drug Shortages Survey</strong></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-78798080166117388722016-10-16T12:43:00.001-07:002016-10-16T12:43:07.097-07:00What are the major challenges that pharmaceutical end users experience with their packaging systems?<div style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25; margin-top: 1.5em;">
There are a couple of significant challenges that pharmaceutical manufacturers may experience in selecting and implementing packaging systems. One of these challenges is posed by the growing trend toward prefilled syringes for liquid injectables. Prefilled syringes offer a much higher degree of performance than traditional vials by eliminating the dosage preparation necessary at the hospital. However, the implementation of prefilled syringes expands the validation process for the drug manufacturer.</div>
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<img alt="PM1609 Insights" class="right" height="352" src="https://www.pharmamanufacturing.com/assets/Media/2016/1608/PM1609-Insights.png" style="border: 0px; box-sizing: inherit; display: block; float: none; height: auto; margin: 0px auto; max-width: none; padding: 0px; width: 222px;" title="" width="232" /><br />
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Jerry Martin, pharmaceutical and life sciences consultant to PMMI, The Association of Packaging and Processing Technologies</div>
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Another challenge stems from the new standard on the qualification of materials for packaging systems with regard to extractables and leachables. Chemicals that can migrate out of the packaging materials and into the dosage form are a concern. With advancing analytics technology, there is a push from the FDA to understand what risks are posed by packaging ingredient migration. U.S. Pharmaceutical Convention (USP) is actively working on revising its standards for qualifying plastic packaging materials from the raw material to the final format. It's in the process of being finalized and it will be helpful for the industry to follow those standards. The goal is to establish standard evaluation methods and eventually, threshold limits, out of a consensus of experts.</div>
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<em style="box-sizing: inherit;"><strong style="box-sizing: inherit;">Can you elaborate more on the revision of standards by the USP?</strong></em></div>
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USP has formed an expert committee of volunteers from different reaches of the pharmaceutical and biotech sectors — including testing laboratories, drug manufacturers and component or equipment suppliers — to assess the risks and establish an updated, standardized approach to qualifying materials and packaging systems. The first two new standards published late last year addressed the qualification of component materials and final containers made from those materials. The next standards will address the process equipment side — upstream of filling the final packaging. These are currently in draft form and will be finalized by the end of this year. The next step, slated for 2017, is to generate standards for the suitability of packaging in the final dosage form.</div>
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<strong style="box-sizing: inherit;"><em style="box-sizing: inherit;">When will drug manufacturers be expected to comply with these new standards?</em></strong></div>
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No deadlines are set for compliance. These standards are voluntary. The USP sets the reference standards for the U.S. Food and Drug Administration (FDA). Therefore, pharmaceutical manufacturers that follow the USP standards will not have to go through any extra steps to meet FDA approval. However, pharmaceutical manufacturers that opt not to abide by USP standards will be held accountable by the FDA to provide other proof that the methods of analysis utilized are at least as effective. The USP's guidelines are treated as expectations. If an FDA reviewer questions a practice that complies with USP standards, pharmaceutical manufacturers have a strong scientific basis to stand on.</div>
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<strong style="box-sizing: inherit;"><em style="box-sizing: inherit;">At this particular juncture in time, what is driving the need for these new USP standards?</em></strong></div>
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Packaging systems are becoming more and more complex. I recently read about a biological that is packaged in an automatically timed, self-injection device that patients can wear on their stomachs. When a packaging system was just a vial in a box, there were far fewer components to evaluate. We're moving into a domain where the drug and the device are a package deal, but assessed by different teams at the FDA. The trend toward more complex delivery systems just doesn't always fit into the organizational structure of that agency. The FDA addressed this through the Office of Combination Products and new guidance. Creating a standardized set of expectations will make oversight of these increasingly complex packaging systems easier for all parties.</div>
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<strong style="box-sizing: inherit;"><em style="box-sizing: inherit;">How has this trend toward complex packaging systems affected the general supply chain?</em></strong></div>
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Pharmaceutical manufacturers certainly want to ensure that drugs, especially biologicals, are kept at the right temperature through the course of the supply chain. While we haven't seen many instances where temperature control of the drug has compromised the delivery device, temperature control is becoming more sophisticated with tracers that monitor the temperature and maintaining it through electronic signal so that the operators detect any deviation before the product goes bad. The added complexity is bound to necessitate greater utilization of the Internet of Things (IoT) to provide a higher sense of security and environmental control. These methods are being investigated now. On the topic of track-and-trace, sophisticated monitoring devices can help serve to authenticate original products when the threat of counterfeits loom over a drug.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-83859400244126271912016-10-16T12:41:00.003-07:002016-10-16T12:41:26.697-07:00Establishing a Root Cause Failure Analysis Program at a Pharma Facility<div style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 14px; line-height: 1.25;">
<span style="color: #838383; font-size: 12px;">By Anil Agrawalla, CMRP, Life Cycle Engineering</span></div>
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Your clean steam generator system stops and alarms. Production halts; operations quickly calls maintenance. Maintenance jumps into action and determines that the bearing seized in the feed water pump. A bearing order is expedited through procurement, maintenance efficiently makes the repair the next morning, and the production team runs tests before putting the system back into operation. Corrective actions are created to ensure that the bearing is stocked in the MRO storeroom, and to double frequency of the pump’s preventive maintenance. The senior leadership team is satisfied with the response and corrective actions, and praises the team for limiting the production delay to just 24 hours.</div>
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Does this scenario sound familiar? A critical piece of equipment fails and the facility scrambles to get the system back to operation. Corrective actions are implemented to reduce future failures, but are done without asking why the equipment failure occurred. Resources aren’t allocated to identify the root cause on a significant failure like this, yet resources are dedicated to other issues that don’t seem as important to the business. This gap creates the opportunity to implement a Root Cause Failure Analysis (RCFA) program.</div>
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Implementing an RCFA program at a pharmaceutical manufacturing site can be a large undertaking, especially for failures that don’t affect product quality. Site resources and priority are given to investigations for quality-related issues due to the strict nature of FDA and regulatory requirements for issues that can impact a patient’s health. Non-quality-related investigations can significantly impact business but often don’t get the same scrutiny as quality investigations. </div>
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<span style="box-sizing: inherit; font-size: 1.4rem;">Including non-quality-related failures in a well-planned RCFA program can bring substantial value to the company. Three factors are key to program success when implementing an RCFA program in a pharmaceutical environment:</span></div>
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<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0px;">Having a well-defined process that provides a strong foundation / framework</li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;">Aligning the RCFA program with the existing quality investigation process to help ease the introduction to the site and reduce the resources required for implementation</li>
<li style="box-sizing: inherit; font-size: 1em; line-height: 1.25; margin: 0.6em 0px 0px;">Communicating the program value to senior leadership and the rest of the site to achieve site-wide adoption and ensure persistency.</li>
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A six-step RCFA process will provide the needed framework. Alignment with the existing quality investigations occur within each step. </div>
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<strong style="box-sizing: inherit;">STEP ONE: NOTIFICATION</strong>The notification step is a pre-defined set of triggers that initiate an RCFA investigation whenever a failure event results in significant loss to the facility. As a general note, an RCFA program can investigate any type of significant event. For the scope of this program, events are intended for equipment-related failures. Although the initial failure symptoms experienced are equipment-related, these failures may end up having root causes that are not directly attributed to the equipment.</div>
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The triggers used to initiate an RCFA investigation should encompass all aspects of the business including major safety incidents, environmental violations, product quality issues, high maintenance costs, and production downtime events. The triggers should look for single, significant failure events as well as smaller, repetitive failures that occur frequently. Though a single, smaller failure would normally not be investigated, the chronic and repetitive nature can lead to a significant cumulative cost to the company. The type of trigger and its trigger level need to be customized for each company. The triggers should be set so that the cost of the root cause investigation is less than the business cost experienced by the company.</div>
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The Quality, Safety, and Environmental departments may already have their own investigation triggers for failure events that have a quality or safety effect. Since the process, tools used, and goals of those investigations are similar to ones used in an RCFA program, a separate analysis is generally not needed. A maintenance or reliability employee trained in the site’s RCFA program should join the existing investigation process to help with identifying and mitigating the root causes. High maintenance repair costs and production downtime can have a significant financial impact, so both of these can be triggers for an investigation. Triggers for chronic events can include repetitive causes that are trended in the CMMS’s failure coding, or excessive stoppages noticed on the production floor during production runs. </div>
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A process map of the Notification step, shown in the figure below, displays an example set of triggers. As the figure shows, there is a clear definition and level for each trigger, which reduces the ambiguity of when an RCFA should be triggered. The success factor for this first step of the RCFA program is to ensure that the rest of the facility is aware of the RCFA program and its triggers. All employees, from operators to directors, are responsible for identifying equipment failures that trigger an RCFA investigation and notifying the RCFA process owner.</div>
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<img alt="A process map of the Notification step" class="left" height="201" src="https://www.pharmamanufacturing.com/assets/Media/2016/1610/Rootcause1.png" style="border: 0px; box-sizing: inherit; display: block; float: left; height: auto; margin: 5px 20px 10px 0px; max-width: 100%; padding: 0px;" title="" width="476" /></div>
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<strong style="box-sizing: inherit;">STEP 2: CLARIFICATION</strong>Clarification entails the gathering of information necessary to analyze the failure events. Once an RCFA is triggered, an RCFA facilitator should be quickly assigned to gather any evidence or data related to the triggered event before the evidence disappears. The evidence can range from physical parts, data logs, manufacturing batch records, or interviews from employees involved in the event. It is critical for the RCFA facilitator to be skilled in investigation techniques, particularly those involving interviewing personnel. The facilitator should be able to gather factual event information without alienating the interviewees. These techniques are often taught through the Quality department for quality investigations, and can be utilized to train the RCFA facilitator.</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-35725363767224561692016-10-16T12:38:00.000-07:002016-10-16T12:38:07.377-07:00Three Laws of HVAC Optimization<div class="breadcrumbs noindex" itemscope="" itemtype="http://data-vocabulary.org/Breadcrumb" style="background-color: white; box-sizing: inherit; font-family: TeXGyreHeros, Arial, sans-serif; font-size: 1.2rem; font-weight: bold; margin-bottom: 16px;">
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Three Laws of HVAC Optimization</h1>
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HVAC systems hold the key to energy efficiency in pharma</h2>
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By Alaina Bookstein, Optimum Energy</div>
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Oct 05, 2016</div>
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Pharmaceutical manufacturing facility executives increasingly face demands to cut operational costs and drive down energy and water use to meet corporate sustainability goals. Heating, ventilation and air conditioning (HVAC) systems are a natural place to look for such savings: these systems typically account for 65 percent of the energy used in pharmaceutical manufacturing facilities, according to research by Lawrence Berkeley National Laboratory, and chilled water plants consume large amounts of water every day. Optimizing HVAC systems to minimize energy and water use clearly has enormous financial and sustainability benefits.</div>
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HVAC efficiency projects, however, often fail to deliver on their promise. In environments where maintaining precise ambient conditions is essential to product quality, even new, state-of-the-art HVAC systems lose operational efficiency after installation. System operators, faced with pressing operational needs, understandably will take control, overriding set points and sacrificing efficiency.</div>
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The HVAC efficiency upgrades that succeed aim for system-level optimization (mechanical systems working at peak effectiveness, all the time) rather than simple individual component efficiency. The engineers at Optimum Energy have broken down this approach into three laws of optimization:</div>
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<strong style="box-sizing: inherit;">1. Measurement comes first.</strong> Without an accurate measure of energy use by each piece of equipment in the system, it is impossible to accurately predict and report the impact of varying conditions on the system. In other words, if you can’t measure it, you can’t optimize it.</div>
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<strong style="box-sizing: inherit;">2. Focus on the system.</strong> If an optimization plan focuses on installing the most efficient pieces of equipment without considering how to maximize performance of the whole system, it won’t capture the total available efficiency. Holistic, automatic optimization of HVAC systems typically increases energy efficiency by an additional 10 to 25 percent over just installing new equipment.</div>
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<strong style="box-sizing: inherit;">3. Optimization must be automatic, dynamic and continuous.</strong> To achieve maximum efficiency, optimization must be a real-time dynamic process, not a static set-and-forget process. Operational control of a pharmaceutical manufacturing plant or research laboratory must be based on real-time inputs and adjustments. Without that data and automation, you cannot fully optimize the HVAC system while maintaining strict environmental conditions.<br />
Following these laws can lead to impressive results. For example, Amgen’s Thousand Oaks campus in southern California improved its average efficiency rating by 33 percent and saved $990,000 and 11 million kWh annually by optimizing three chiller plants and upgrading its building automation system (BAS).</div>
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The facility installed Optimum Energy’s OptimumLOOP technology, which works through the BAS to continuously and dynamically adapt the chilled water plant’s operations to conform with fluctuating loads, weather and occupancy conditions. A connection to the cloud-based OptiCx software platform increased visibility into plant operations, which revealed that a lead plant was operating extremely inefficiently.</div>
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Pharmaceutical facility directors can wring savings out of even the most demanding environments — with new or existing equipment — by following the laws of optimization.</div>
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</article>Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-80963768122082808592016-10-16T12:31:00.001-07:002016-10-16T12:31:09.112-07:00cell and Gene Therapy Manufacturing 2016<div class="title" style="background-color: white; box-sizing: border-box; color: #3a3a3a; font-family: source-sans-pro; font-size: 14px;">
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cell and Gene Therapy Manufacturing 2016</h1>
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Contributor: Miss Chanice Henry</div>
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Posted: 09/20/2016</div>
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Earlier this month, Industry members gathered to tackle challenges and contribute to the discussion surrounding cell and gene therapies and their manufacture.</div>
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The dominant notion that emerged from the conference was the emphasis on the management of the product’s starting material in the manufacture of <a href="http://www.coldchainiq.com/supply-chain-security/articles/a-new-study-rfid-safe-for-biologics/" style="background-color: transparent; box-sizing: border-box; color: #126393; text-decoration: none;">cell and gene therapie</a>s. The transit of these therapies should be perceived not as merely shipping but in fact mapping out a chain of identity and custody to ensure materials are fully preserved. Also, considering and planning for scaling-up early on in the process.</div>
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<span style="box-sizing: border-box;">A range of topics were addressed on site including, scalability, <a href="http://www.pharma-iq.com/pre-clinical-discovery-and-development/articles/the-top-10-pharmaceutical-biotechnology-r-d-invest/index.cfm" style="background-color: transparent; box-sizing: border-box; color: #126393; text-decoration: none;">gene modified t-cell</a>s, regulatory requirements, closed system processing and AAV based gene therapy vectors. The <a href="http://www.coldchainiq.com/supply-chain-security/white-papers/pharma-supply-chain-360-ebook/" style="background-color: transparent; box-sizing: border-box; color: #126393; text-decoration: none;">logistics of transporting</a> a cell therapy to the patient with a reasonable cost of goods was examined. The reasonable cost of goods is understood as being the total price of all services and goods within the process of the therapy and its delivery. It was noted that logistics costs can extend up to 60% of the overall costs of the therapy.</span></div>
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<span style="box-sizing: border-box;"><img alt="Cell 1" height="227" src="https://plsadaptive.s3.amazonaws.com/site/resize/remote/5f68f9dc03e508f4cec1efee02ed27dc-296x227.png?ecth0JNgZ_Zrs8XVwCpP40GnOU3unEWK" style="border: 0px; box-sizing: border-box; vertical-align: middle;" title="Cell 1" width="296" /></span></div>
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<span style="box-sizing: border-box;">Many experts at the event stressed that going commercial needs to be considered in the initial outset rather than just when the scaling up is needed. </span><span style="box-sizing: border-box;"> </span><span style="box-sizing: border-box;">System integration is vital to uplifting volumes.</span></div>
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<span style="box-sizing: border-box;">Questions were asked on whether the patients should be brought to the therapy at the production site rather than vice versa due to the added controls needed. However, it was noted that this isn't always suitable in some cases as patients can be critically Ill, therefore international travel is not always an option.</span></div>
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<span style="box-sizing: border-box;">Another key subject posed by speaker Dawn Hiles, Senior Biomedical Scientist, Production Manager for Cellular Therapies, Newcastle University was the focus on sterility assurance challenges in the manufacture of advanced therapeutic medicinal products. The entire whole production process needs to be designed to ensure that the product has the most minimal risk of contamination. Contamination can occur at any stage and the initial materials themselves need to be assessed.</span></div>
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<span style="box-sizing: border-box;">Other experts onsite included the likes of, Sascha Sonnenberg, President of Global CTS Sales and Operations, Marken, Elena Meurer, Head of Pharmaceutical and Technical Development at Apceth, Miguel Forte of TXCell and Antoine Heron of Merck Life Sciences.</span></div>
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<span style="box-sizing: border-box;">Companies present included </span><span style="box-sizing: border-box;">Cell & Gene Therapy Catapult, </span><span style="box-sizing: border-box;">Plasticell, World Courier and </span><span style="box-sizing: border-box;">Cellular Therapeutics.</span></div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-92155765361430839632016-10-16T12:26:00.002-07:002016-10-16T12:26:37.155-07:00Crystal Clear Imaging for Nanoscale Molecular Arrangements<div class="panel-pane pane-views pane-non-featured-content-title-widget" style="color: #222222; font-family: FengardoNeue, sans-serif; font-size: 15px; padding: 0px 30px;">
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<span class="views-field views-field-created" style="color: grey; float: left; padding: 0px 10px 0px 0px;"><span class="field-content">Fri, 10/14/2016 - 12:38pm</span></span><span class="views-field views-field-disqus-comment-count" style="color: grey; float: left; padding: 0px 10px 0px 0px;"><span class="field-content"><a data-disqus-identifier="uuid/4a618770-cbb4-4741-aed8-2d848f6a093d" href="http://www.cemag.us/news/2016/10/crystal-clear-imaging-nanoscale-molecular-arrangements#disqus_thread" style="color: grey; text-decoration: none;"></a></span></span><div class="views-field views-field-views-conditional">
<span class="field-content">by Glenn Roberts Jr., Berkeley Lab</span></div>
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Infrared light (pink) produced by Berkeley Lab’s Advanced Light Source synchrotron (upper left) and a conventional laser (middle left) is combined and focused on the tip of an atomic force microscope (gray, lower right), where it is used to measure nanoscale details in a crystal sample (dark red). Image: Berkeley Lab, CU-Boulder</div>
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Detailing the molecular makeup of materials — from solar cells to organic light-emitting diodes (LEDs) and transistors, and medically important proteins — is not always a crystal-clear process.</div>
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To understand how materials work at these microscopic scales, and to better design materials to improve their function, it is necessary to not only know all about their composition but also their molecular arrangement and microscopic imperfections.</div>
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Now, a team of researchers working at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) has demonstrated infrared imaging of an organic semiconductor known for its electronics capabilities, revealing key nanoscale details about the nature of its crystal shapes and orientations, and defects that also affect its performance.</div>
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To achieve this imaging breakthrough, researchers from Berkeley Lab’s Advanced Light Source (ALS) and the University of Colorado-Boulder (CU-Boulder) combined the power of infrared light from the ALS and infrared light from a laser with a tool known as an atomic force microscope. The ALS, a synchrotron, produces light in a range of wavelengths or “colors” — from infrared to X-rays — by accelerating electron beams near the speed of light around bends.</div>
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The researchers focused both sources of infrared light onto the tip of the atomic force microscope, which works a bit like a record-player needle — it moves across the surface of a material and measures the subtlest of surface features as it lifts and dips.</div>
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The technique, detailed in a recent edition of the journal <em>Science Advances</em>, allows researchers to tune the infrared light in on specific chemical bonds and their arrangement in a sample, show detailed crystal features, and explore the nanoscale chemical environment in samples.</div>
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“Our technique is broadly applicable,” says Hans Bechtel, an ALS scientist. “You could use this for many types of material — the only limitation is that it has to be relatively flat” so that the tip of the atomic force microscope can move across its peaks and valleys.</div>
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Markus Raschke, a CU-Boulder professor who developed the imaging technique with Eric Muller, a postdoctoral researcher in his group, says, “If you know the molecular composition and orientation in these organic materials then you can optimize their properties in a much more straightforward way.</div>
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“This work is informing materials design. The sensitivity of this technique is going from an average of millions of molecules to a few hundred, and the imaging resolution is going from the micron scale (millionths of an inch) to the nanoscale (billionths of an inch),” he says.</div>
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The infrared light of the synchrotron provided the essential wide band of the infrared spectrum, which makes it sensitive to many different chemicals’ bonds at the same time and also provides the sample’s molecular orientation. The conventional infrared laser, with its high power yet narrow range of infrared light, meanwhile, allowed researchers to zoom in on specific bonds to obtain very detailed imaging.</div>
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“Neither the ALS synchrotron nor the laser alone would have given us this level of microscopic insight,” Raschke says, while the combination of the two provided a powerful probe “greater than the sum of its parts.”</div>
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Raschke a decade ago first explored synchrotron-based infrared nano-spectroscopy using the BESSY synchrotron in Berlin. With his help and that of ALS scientists Michael Martin and Bechtel, the ALS in 2014 became the first synchrotron to offer nanoscale infrared imaging to visiting scientists.</div>
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The technique is particularly useful for the study and understanding of so-called “functional materials” that possess special photonic, electronic, or energy-conversion or energy-storage properties, he notes.</div>
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In principle, he adds, the new advance in determining molecular orientation could be adapted to biological studies of proteins. “Molecular orientation is critical in determining biological function,” Raschke said. The orientation of molecules determines how energy and charge flows across from cell membranes to molecular solar energy conversion materials.</div>
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Bechtel says the infrared technique permits imaging resolution down to about 10 to 20 nanometers, which can resolve features up to 50,000 times smaller than a grain of sand.</div>
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The imaging technique used in these experiments, known as “scattering-type scanning near-field optical microscopy,” or s-SNOM, essentially uses the atomic force microscope tip as an ultrasensitive antenna, which transmits and receives focused infrared light in the region of the tip. Scattered light, captured from the tip as it moves over the sample, is recorded by a detector to produce high-resolution images.</div>
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“It’s non-invasive, and it provides information about molecular vibrations,” as the microscope’s tip moves over the sample, Bechtel says. Researchers used the technique to study the crystalline features of an organic semiconductor material known as PTCDA (perylenetetracarboxylic dianhydride).</div>
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Researchers reported that they observed defects in the orientation of the material’s crystal structure that provide a new understanding of the crystals’ growth mechanism and could aid in the design molecular devices using this material.</div>
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The new imaging capability sets the stage for a new National Science Foundation Center, announced in late September, that links CU-Boulder with Berkeley Lab, UC Berkeley, Florida International University, UC Irvine, and Fort Lewis College in Durango, Colo. The center will combine a range of microscopic imaging methods, including those that use electrons, X-rays, and light, across a broad range of disciplines.</div>
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This center, dubbed STROBE for Science and Technology Center on Real-Time Functional Imaging, will be led by Margaret Murnane, a distinguished professor at CU-Boulder, with Raschke serving as a co-lead.</div>
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At Berkeley Lab, STROBE will be served by a range of ALS capabilities, including the infrared beamlines managed by Bechtel and Martin and a new beamline dubbed COSMIC (for “coherent scattering and microscopy”). It will also benefit from Berkeley Lab-developed data analysis tools.</div>
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Other contributors to the work include Benjamin Pollard and Peter van Blerkom, both members of Raschke’s group at CU-Boulder.</div>
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The work was supported by the National Science Foundation. The ALS is a DOE Office of Science User Facility.</div>
Source: Berkeley Lab</div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-1449439636741033292016-05-13T07:28:00.002-07:002016-05-13T07:28:32.978-07:00A Basic Introduction to Clean Rooms<div class="MsoNormal">
<span style="font-family: Arial;"><b><span style="font-size: 16pt;"> </span><span style="font-size: 14pt;"><o:p> </o:p></span></b>A cleanroom is a controlled environment where products are manufactured. It is a room in which the concentration of airborne particles is controlled to specified limits. Eliminating sub-micron airborne contamination is really a process of control. These contaminants are generated by people, process, facilities and equipment. They must be continually removed from the air. The level to which these particles need to be removed depends upon the standards required. The most frequently used standard is the Federal Standard 209E. The 209E is a document that establishes standard classes of air cleanliness for airborne particulate levels in cleanrooms and clean zones. Strict rules and procedures are followed to prevent contamination of the product.</span></div>
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<span style="font-family: Arial;"> The only way to control contamination is to control the total environment. Air flow rates and direction, pressurization, temperature, humidity and specialized filtration all need to be tightly controlled. And the sources of these particles need to controlled or eliminated whenever possible. There is more to a clean room than air filters. Cleanrooms are planned and manufactured using strict protocol and methods. They are frequently found in electronics, pharmaceutical, biopharmaceutical, medical device industries and other critical manufacturing environments.</span></div>
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<span style="font-family: Arial;"> It only takes a quick monitor of the air in a cleanroom compared to a typical office building to see the difference. Typical office building air contains from 500,000 to 1,000,000 particles (0.5 microns or larger) per cubic foot of air. A Class 100 cleanroom is designed to never allow more than 100 particles (0.5 microns or larger) per cubic foot of air. Class 1000 and Class 10,000 cleanrooms are designed to limit particles to 1000 and 10,000 respectively. </span></div>
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<span style="font-family: Arial;"> A human hair is about 75-100 microns in diameter. A particle 200 times smaller (0.5 micron) than the human hair can cause major disaster in a cleanroom. Contamination can lead to expensive downtime and increased production costs. In fact, the billion dollar NASA Hubble Space Telescope was damaged and did not perform as designed because of a particle smaller than 0.5 microns.</span></div>
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<span style="font-family: Arial;"> Once a cleanroom is built it must be maintained and cleaned to the same high standards. This handbook has been prepared to give professional cleaning staff information about how to clean the cleanroom.<b><o:p></o:p></b></span></div>
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<span style="font-family: Arial;"><b> <span style="color: blue;"><o:p></o:p></span></b><span style="color: blue;"><b><span style="font-size: 16pt;">What is Contamination?</span></b></span></span></div>
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<span style="font-family: Arial;"> Contamination is a process or act that causes materials or surfaces to be soiled with contaminating substances. There are two broad categories of surface contaminants: film type and particulates. These contaminants can produce a “killer defect” in a miniature circuit. Film contaminants of only 10 nm (nanometers) can drastically reduce coating adhesion on a wafer or chip. It is widely accepted that particles of 0.5 microns or larger are the target. However, some industries are now targeting smaller particles.</span></div>
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<span style="font-family: Arial;"> A partial list of contaminants is found below. Any of these can be the source for killing a circuit. Preventing these contaminants from entering the cleanroom environment is the objective. It requires a commitment by everyone entering the cleanroom to make it happen. Professional cleaning personnel need to be aware of the importance of controlling contaminants. Strict procedures should be followed whenever entering or cleaning a cleanroom. Compromise is not acceptable when cleaning in a cleanroom.</span></div>
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<big><span style="color: blue; font-family: Arial;"><b>Sources of Contamination<o:p></o:p></b></span></big></div>
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<span style="font-family: Arial;"> This is a partial list of some of the commonly known contaminants that can cause problems in some cleanroom environments. It has been found that many of these contaminants are generated from five basic sources. The facilities, people, tools, fluids and the product being manufactured can all contribute to contamination. Review this list to gain a better understanding of where contamination originates.</span></div>
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<span style="font-family: Arial;"><b>1. Facilities</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Walls, floors and ceilings<o:p></o:p></span></div>
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<span style="font-family: Arial;">Paint and coatings<o:p></o:p></span></div>
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<span style="font-family: Arial;">Construction material (sheet rock, saw dust etc.)<o:p></o:p></span></div>
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<span style="font-family: Arial;">Air conditioning debris<o:p></o:p></span></div>
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<span style="font-family: Arial;">Room air and vapors<o:p></o:p></span></div>
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<span style="font-family: Arial;">Spills and leaks</span></div>
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<span style="font-family: Arial;"><b>2. People</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Skin flakes and oil<o:p></o:p></span></div>
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<span style="font-family: Arial;">Cosmetics and perfume<o:p></o:p></span></div>
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<span style="font-family: Arial;">Spittle<o:p></o:p></span></div>
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<span style="font-family: Arial;">Clothing debris (lint, fibers etc.)<o:p></o:p></span></div>
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<span style="font-family: Arial;">Hair<o:p></o:p></span></div>
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<span style="font-family: Arial;"> <b>3. Tool Generated</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Friction and wear particles<o:p></o:p></span></div>
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<span style="font-family: Arial;">Lubricants and emissions<o:p></o:p></span></div>
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<span style="font-family: Arial;">Vibrations<o:p></o:p></span></div>
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<span style="font-family: Arial;">Brooms, mops and dusters<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b>4. Fluids</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Particulates floating in air<o:p></o:p></span></div>
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<span style="font-family: Arial;">Bacteria, organics and moisture<o:p></o:p></span></div>
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<span style="font-family: Arial;">Floor finishes or coatings<o:p></o:p></span></div>
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<span style="font-family: Arial;">Cleaning chemicals<o:p></o:p></span></div>
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<span style="font-family: Arial;">Plasticizers (outgasses)<o:p></o:p></span></div>
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<span style="font-family: Arial;">Deionized water<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b>5. Product generated</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Silicon chips<o:p></o:p></span></div>
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<span style="font-family: Arial;">Quartz flakes<o:p></o:p></span></div>
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<span style="font-family: Arial;">Cleanroom debris<o:p></o:p></span></div>
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<span style="font-family: Arial;">Aluminum particles<o:p></o:p></span></div>
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<span style="color: blue; font-family: Arial;"><small><small>Key Elements of Contamination Control<o:p></o:p></small></small></span></h1>
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<span style="font-family: Arial;"> <o:p> We will look at several areas of concern to get a better idea of the overall picture of contamination control. These are the things that need to be considered when providing an effective contamination control program.<o:p></o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>HEPA (High Efficiency Particulate Air Filter)</u></b> - These filters are extremely important for maintaining contamination control. They filter particles as small as 0.3 microns with a 99.97% minimum particle-collective efficiency. <o:p></o:p> </span></div>
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<span style="font-family: Arial;"><b><u>CLEANROOM ARCHITECTURE</u></b> - Cleanrooms are designed to achieve and maintain a airflow in which essentially the entire body of air within a confined area moves with uniform velocity along parellel flow lines. This air flow is called laminar flow. The more restriction of air flow the more turbulence. Turbulence can cause particle movement.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>FILTRATION</u></b> - In addition to the HEPA filters commonly used in cleanrooms, there are a number of other filtration mechanisms used to remove particles from gases and liquids. These filters are essential for providing effective contamination control.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>CLEANING</u></b> - Cleaning is an essential element of contamination control. Decisions need to made about the details of cleanroom maintenance and cleaning. Applications and procedures need to be written and agreed upon by cleanroom management and contractors (if used). There are many problems associated with cleaning. Managers need to answer the following questions before proceeding with any cleanroom cleaning program:<o:p></o:p></span></div>
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<span style="font-family: Arial;">1. What is clean?<o:p></o:p></span></div>
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<span style="font-family: Arial;">2. How is clean measured?<o:p></o:p></span></div>
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<span style="font-family: Arial;">3. What cleaning materials can be used in the cleanroom?<o:p></o:p></span></div>
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<span style="font-family: Arial;">4. When can the cleanroom be cleaned?<o:p></o:p></span></div>
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<span style="font-family: Arial;">5. How frequent does it need to be cleaned?<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>CLEANROOM GARMENTS</u></b> - The requirements for cleanroom garments will vary from location to location. It is important to know the local garment requirements of the cleanroom management. Gloves, face masks and head covers are standard in nearly every cleanroom environment. Smocks are being used more and more. Jump suits are required in very clean environments.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>HUMANS IN CLEANROOMS</u></b> - There are both physical and psychological concerns when humans are present in cleanrooms. Physical behavior like fast motion and horseplay can increase contamination. Psychological concerns like room temperature, humidity, claustrophobia, odors and workplace attitude are important. Below are several ways people produce contamination:<o:p></o:p></span></div>
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<span style="font-family: Arial;">1. <b>Body Regenerative Processes</b>-- Skin flakes, oils, perspiration and hair.<o:p></o:p></span></div>
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<span style="font-family: Arial;">2. <b>Behavior</b>-- Rate of movement, sneezing and coughing.<o:p></o:p></span></div>
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<span style="font-family: Arial;">3. <b>Attitude</b>-- Work habits and communciation between workers.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> <o:p> People are a major source of contamination in the cleanroom. Look at the people activies listed below. Notice the number of particles produced per minute during these activities.<o:p></o:p></o:p></span></div>
<table border="1" style="width: 100%px;"><tbody>
<tr><td width="50%"><b><span style="font-family: Arial;">PEOPLE ACTIVITY</span></b></td><td width="50%"><span style="font-family: Arial;"><b>PARTICLES/MINUTE (0.3 microns and larger</b><span style="font-size: 14pt;"><o:p></o:p>)</span></span></td></tr>
<tr><td width="50%"><span style="font-family: Arial;">Motionless (Standing or Seated)</span></td><td width="50%"><span style="font-family: Arial;">100,000<o:p></o:p></span></td></tr>
<tr><td width="50%"><span style="font-family: Arial;">Walking about 2 mph</span></td><td width="50%"><span style="font-family: Arial;">5,000,000<o:p></o:p></span></td></tr>
<tr><td width="50%"><span style="font-family: Arial;">Walking about 3.5 mph</span></td><td width="50%"><span style="font-family: Arial;">7,000,000<o:p></o:p></span></td></tr>
<tr><td width="50%"><span style="font-family: Arial;">Walking about 5 mph</span></td><td width="50%"><span style="font-family: Arial;">10,000,000</span></td></tr>
<tr><td width="50%"><span style="font-family: Arial;">Horseplay</span></td><td width="50%"><span style="font-family: Arial;">100,000,000</span></td></tr>
</tbody></table>
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<span style="font-family: Arial;"> <o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>COMMODITIES</u></b> - Care is taken when selecting and using commodity items in cleanrooms. Wipers, cleanroom paper and pencils and other supplies that service the cleanroom should be carefully screened and selected. Review of the local cleanroom requirements for approving and taking these items into the cleanroom are essential. In fact, many cleanroom managers will have approval lists of these types of items.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>COSMETICS</u></b> - Many cosmetics contain sodium, magnesium, silicon, calcium, potassium or iron. These chemicals can create damaging particles. Cleanroom managers may ban or restrict cosmetics in the cleanroom. This is usually dependent upon the threat to the product being made in the cleanroom. A recent mirror on a space telescope was fogged up from the cologne that was present in the cleanroom.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>MEASUREMENT AND INSTRUMENTATION </u></b> - Some important measurements related to contamination control are particle count, air flow & velocity, humidity, temperature and surface cleanliness. Cleanroom managers usually have specific standards and/or instruments to measure these factors.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b><u>ELECTROSTATIC DISCHARGE (ESD)</u></b> - When two surfaces rub together an electrical charge can be created. Moving air creates a charge. People touching surfaces or walking across the floor can create a triboelectric charge. Special care is taken to use ESD protective materials to prevent damage from ESD. Cleaning managers should work with their personnel to understand where these conditions may be present and how to prevent them.<o:p></o:p></span></div>
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<span style="color: blue; font-family: Arial;"><big><strong><big>Cleaning Procedures for Clean Rooms<o:p></o:p></big></strong></big></span></div>
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<span style="font-family: Arial;"> <o:p></o:p>What follows are some recommended procedures for cleaning cleanrooms. It is important to emphasize that these procedures are guidelines and not standards or rules. The procedures listed here are routine cleaning tasks. Local cleanroom cleaning procedures may supercede the ones listed here. It is important for cleaning managers to review all cleaning procedures to be used in a cleanroom with the cleanroom management. A detailed cleaning schedule should be prepared for every cleanroom. Here are some procedures to be completed when cleaning a Class 10,000 cleanroom:<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b>Cleaning Procedures for a Class 10,000 Cleanroom</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Housekeeping maintenance of the cleanroom and restricted areas is essential to assure quality. Cleaning of a cleanroom should be performed on a daily basis. Improper cleaning of the cleanroom can lead to contamination and a loss in end user product quality. Proper selection of equipment and materials is important for proper cleaning. Only products that have proven cleanroom performance records should be considered for use in cleanrooms. These products should be listed and all vendors should be informed about the strict policies of how products are qualified. All procedures should be strictly enforced. Below are some examples of how to organize the cleaning to be done in a cleanroom. These are NOT schedules or exact procedures. They are guidelines for preparing work procedures and schedules. Local requirements must be included in any cleaning program.<o:p></o:p></span></div>
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<strong><span style="font-family: Arial;">List of Some of Equipment and Supplies Needed to Clean the Cleanroom<o:p></o:p></span></strong></div>
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<span style="font-family: Arial;">(All supplies must meet the Class 10,000 minimum requirements)<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 1. Cleaning and disinfecting solutions<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 2. Cleanroom mops<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 3. Cleanroom vacuum cleaner (if allowed)<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 4. Cleanroom wipers<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 5. Cleanroom mop bucket and wringer</span></div>
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<strong><span style="font-family: Arial;">List of Cleaning Tasks to be Completed in the Cleanroom<o:p></o:p></span></strong></div>
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<span style="font-family: Arial;"><i>(</i>Frequency may vary depending upon local requirements)<o:p></o:p> <o:p></o:p></span></div>
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<span style="font-family: Arial;"> 1. Cleaning of all work surfaces in the controlled environment.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 2. Vacuuming (if allowed) of the floors and work surfaces.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 3. Emptying of appropriate trash and waste.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 4. Cleaning of the doors, door frames and lockers in the pre-staging area and gowning areas using the approved cleaning solution.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> 5. Mop gowning and cleanroom floors.<o:p></o:p></span></div>
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<span style="font-family: Arial;"><b>Cleaning Procedures for a Class 1000 Cleanroom</b><o:p></o:p></span></div>
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<span style="font-family: Arial;">Below is a sample of a cleaning program in a Class 1000 Cleanroom. This is only a sample of a program. Local standards and requirements must be followed.<o:p></o:p></span></div>
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<tr><td width="13%"><big><strong>Area</strong></big></td><td width="53%"><big><strong>Description of Work</strong></big></td><td width="34%"><big><strong>Frequency</strong></big></td></tr>
<tr><td width="13%">101</td><td width="53%"><span style="font-family: Arial;">Change tacky mats</span></td><td width="34%"><span style="font-family: Arial;">Every 2 hours</span></td></tr>
<tr><td width="13%">102</td><td width="53%"><span style="font-family: Arial;">Wet mop with approved mop, cleaner & DI water</span></td><td width="34%"><span style="font-family: Arial;">2 times per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">103</td><td width="53%"><span style="font-family: Arial;">Dust mop (if allowed)</span></td><td width="34%"><span style="font-family: Arial;">2 times per shift</span></td></tr>
<tr><td width="13%">104</td><td width="53%"><span style="font-family: Arial;">Remove trash, sweep, mop with appropriate cleaner wipe down tables and coffee area, clean walls and recycle cans</span></td><td width="34%"><span style="font-family: Arial;">1 time per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">105</td><td width="53%"><span style="font-family: Arial;">Vacuum entry mats, sweep and mop floors</span></td><td width="34%"><span style="font-family: Arial;">1 time per shift</span></td></tr>
<tr><td width="13%">106</td><td width="53%"><span style="font-family: Arial;">Mop floor with pre-burnish cleaner and tap water</span></td><td width="34%"><span style="font-family: Arial;">1 time per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">107</td><td width="53%"><div class="MsoNormal">
<span style="font-family: Arial;">Remove trash. Always wear gloves. Never take waste containers inside cleanrooms.</span></div>
</td><td width="34%"><span style="font-family: Arial;">1 time per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">108</td><td width="53%"><span style="font-family: Arial;">Wet mop floors</span></td><td width="34%"><span style="font-family: Arial;">1 time per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">109</td><td width="53%"><span style="font-family: Arial;">Remove acid and solvent trash</span></td><td width="34%"><span style="font-family: Arial;">1 time per shift<o:p></o:p></span></td></tr>
<tr><td width="13%">110</td><td width="53%"><span style="font-family: Arial;">Clean and replenish dispenser in all restrooms</span></td><td width="34%"><span style="font-family: Arial;">3 times per week</span></td></tr>
<tr><td width="13%">111</td><td width="53%"><span style="font-family: Arial;">Vacuum floor (if allowed)</span></td><td width="34%"><span style="font-family: Arial;">2 times per week<o:p></o:p></span></td></tr>
<tr><td width="13%">112</td><td width="53%"><div class="MsoNormal">
<span style="font-family: Arial;">Clean stainless steel pass throughs with s/s cleaner<o:p></o:p> and appropriate wipes</span></div>
</td><td width="34%"><span style="font-family: Arial;">1 time per week<o:p></o:p></span></td></tr>
</tbody></table>
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<span style="font-family: Arial;">The list above is a sample of some of the common tasks that need to be performed in a Class 1000 cleanroom. The list is not exhaustive. But gives some ideas of how to prepare work schedules and procedures. An assessment of the cleanroom in conjunction with cleanroom management will help define these tasks and frequencies.</span></div>
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<span style="font-family: Arial;"><b>Cleaning Procedures for a Class 100 Cleanroom</b><o:p></o:p></span></div>
<table border="1" style="width: 100%px;"><tbody>
<tr><td width="12%"><strong><big>Zone</big></strong></td><td width="54%"><strong><big>Procedure</big></strong></td><td width="34%"><strong><big>Frequency</big></strong></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 1a</span></td><td width="54%"><span style="font-family: Arial;">Trash removal</span></td><td width="34%"><span style="font-family: Arial;">Once daily</span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Mop walkways</span></td><td width="34%"><span style="font-family: Arial;">Once a week</span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Wipe down horizontal surfaces</span></td><td width="34%"><span style="font-family: Arial;">Once monthly<o:p></o:p></span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 1b</span></td><td width="54%"><span style="font-family: Arial;">Pull tacky mats</span></td><td width="34%"><span style="font-family: Arial;">Every 2 hours<o:p></o:p></span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 1c</span></td><td width="54%"><span style="font-family: Arial;">Mop and trash removal</span></td><td width="34%"><span style="font-family: Arial;">Once daily</span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Wipe down walls and trim</span></td><td width="34%"><span style="font-family: Arial;">Once a week</span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 1d</span></td><td width="54%"><span style="font-family: Arial;">Mop and trash removal</span></td><td width="34%"><span style="font-family: Arial;">Once daily</span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Wipe walls and trim</span></td><td width="34%"><span style="font-family: Arial;">Once a week<o:p></o:p></span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 2a</span></td><td width="54%"><span style="font-family: Arial;">Mop </span></td><td width="34%"><span style="font-family: Arial;">Twice a shift<o:p></o:p></span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Wipe walls and trim</span></td><td width="34%"><span style="font-family: Arial;">Once a week<o:p></o:p></span></td></tr>
<tr><td width="12%"> </td><td width="54%"><span style="font-family: Arial;">Vacuum</span></td><td width="34%"><span style="font-family: Arial;">Once monthly</span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 2b</span></td><td width="54%"><span style="font-family: Arial;">Mop and trash removal</span></td><td width="34%"><span style="font-family: Arial;">Once per shift<o:p></o:p></span></td></tr>
<tr><td width="12%"><span style="font-family: Arial;">Zone 2c</span></td><td width="54%"><span style="font-family: Arial;">Wipe down walls, windows, doors, trim, showers,<o:p></o:p> passthroughs and fire extinguishers.</span></td><td width="34%"><span style="font-family: Arial;">Once a week<o:p></o:p></span></td></tr>
</tbody></table>
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<span style="font-family: Arial;">The list above is a sample of some of the common tasks that need to be performed in a Class 100 cleanroom. The list is not exhaustive. But gives some ideas of how to prepare work schedules and procedures. An assessment of the cleanroom in conjunction with cleanroom management will help define these tasks and frequencies.<o:p></o:p><b><o:p></o:p></b></span></div>
<h2>
<span style="color: blue; font-family: Arial;"><small>General Cleanroom Regulations<o:p></o:p></small></span></h2>
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<span style="font-family: Arial;">Below is a list of general regulations recommended as a<u> minimum</u> for the successful operation of a cleanroom. All professional cleaning personnel should be aware and follow these regulations at all times.<o:p></o:p></span></div>
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<span style="font-family: Arial;">1. All personal items such as keys, watches, rings, matches, lighters and cigarettes should be stored in the personal locker outside the gowning room.<o:p></o:p></span></div>
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<span style="font-family: Arial;">2. Valuable personal Items such as wallets may be permitted in the cleanroom provided they are NEVER removed from beneath the cleanroom garments.<o:p></o:p></span></div>
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<span style="font-family: Arial;">3. NO eating, smoking or gum chewing allowed inside the cleanroom.<o:p></o:p></span></div>
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<span style="font-family: Arial;">4. Only garments approved for the cleanroom should be worn when entering.<o:p></o:p></span></div>
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<span style="font-family: Arial;">5. NO cosmetics shall be worn in the cleanrooms. This includes: rouge, lipstick, eye shadow, eyebrow pencil, mascara, eye liner, false eye lashes, fingernail polish, hair spray, mousse, or the heavy use of aerosols, after shaves and perfumes.</span></div>
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<span style="font-family: Arial;">6. Only approved cleanroom paper shall be allowed in the cleanroom.<o:p></o:p></span></div>
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<span style="font-family: Arial;">7. Approved ball point pens shall be the only writing tool used.<o:p></o:p></span></div>
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<span style="font-family: Arial;">8. Use of paper or fabric towels are prohibited. Use of hand dryers equipped with HEPA filters are suggested.<o:p></o:p></span></div>
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<span style="font-family: Arial;">9. Gloves or finger cots should not be allowed to touch any item or surface that has not been thoroughly cleaned.</span></div>
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<span style="font-family: Arial;">10. Only approved gloves, finger cots (powder-free), pliers, tweezers should be used to<br />handle product. Finger prints can be a major source of contamination on some products.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">11. Solvent contact with the bare skin should be avoided. They can remove skin oils and increase skin flaking.<o:p></o:p></span></div>
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<span style="font-family: Arial;">12. Approved skin lotions or lanolin based soaps are sometimes allowed. These can reduce skin flaking.<o:p></o:p></span></div>
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<span style="font-family: Arial;">13. All tools, containers and fixtures used in the cleaning process should be cleaned to the same degree as the cleanroom surfaces. All of these items are a source of contamination.<o:p></o:p></span></div>
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<span style="font-family: Arial;">14. NO tool should be allowed to rest on the surface of a bench or table. It should be place on a cleanroom wiper.<o:p></o:p></span></div>
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<span style="font-family: Arial;">15. Only cleanroom approved wipers are allowed to be used. The wipers must be approved for the Class of cleanroom being cleaned.<o:p></o:p></span></div>
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<span style="font-family: Arial;">16. ALL equipment, materials and containers introduced into a sterile facility must be subjected to stringent sterilization prior to entrance.<o:p></o:p></span></div>
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<span style="font-family: Arial;">17. NO ONE who is physically ill, especially with respiratory or stomach disorders, may enter a sterile room. This is a good practice in any cleanroom environment.<o:p></o:p></span></div>
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<span style="font-family: Arial;"> <o:p></o:p><b>Personal Actions Typically Prohibited in Cleanrooms</b><o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">1. Fast motions such as running, walking fast or horseplay.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">2. Sitting or leaning on equipment or work surfaces.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">3. Writing on equipment or garments.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">4. Removal of items from beneath the cleanroom garments.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><o:p></o:p>5. Wearing the cleanroom garment outside the cleanroom.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">6. Wearing torn or soiled garments.</span></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-32970645454095263442016-05-13T07:15:00.002-07:002016-05-13T07:15:32.111-07:00Cleanroom Air Flow Principles<span style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">are facilities designed for conducting research or manufacturing products that require extremely clean environments. Typically, cleanrooms employ a broad range of techniques to prevent air particles, bacteria, and other contaminants from entering the workspace, often by means of employee dress code and washing, pass-thru lockers and chambers, and intensive detail to cleaning. However, one of the major forces keeping a cleanroom particle free is the air filter system. Cleanrooms employ many different types of filters, including HEPA filters<img alt="" src="http://www.thomasnet.com/images/suppliers-small.png" style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;" /> and ULPA filters<img alt="" src="http://www.thomasnet.com/images/suppliers-small.png" style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;" />, but there are two standard air flow patterns that are consistently used: laminar flow and turbulent flow.</span></span><o:p style="background-color: white; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px;"><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p><span style="background-color: white; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px;"></span><br />
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><b style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanroom Basics </b></span></span><b style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><o:p></o:p></b><b style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></b></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanrooms are necessary for various kinds of scientific research that require particle- and bacteria-free environments. For example, when scientists grow cultures, it is important to reduce the introduction of other bacteria so that results will not be compromised. Manufacturing various kinds of products like microprocessors also requires particle-free environment, because even a human hair contacting the small chips of a microprocessor can inhibit or destroy functionality.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanrooms are either hard- or soft-walled. A hard wall cleanroom is a permanent structure or part of a larger permanent structure, while a soft wall cleanroom can be transported or augmented depending on requirements, and primarily exists within a larger, permanent structure. Modular, soft wall cleanrooms are needed for medical emergencies or when smaller runs of environment-sensitive materials are produced within a larger facility.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanrooms are graded depending on how clean the air in the facility is. There are two standards used for this determination: the ISO and United States federal standards. <a href="http://www.unc.edu/~rowlett/units/scales/viscosity.html" style="background: transparent; color: #70a0cf; margin: 0px; padding: 0px; text-decoration: none; vertical-align: baseline;">ISO grades</a> are numbered sequentially, advancing from 1. A cleanroom graded ISO 1 contains ten or fewer particles per 0.1 micrometer cubed area. A cleanroom graded ISO 2 contains 100 or fewer particles per 0.1 micrometer cubed area. The rest of the series feature the amount of particles rising by a factor of 10 per level. US federal standards are numbered 10, 100, 1000, etc., with the lower class number representing a cleaner facility. Class 1 cleanrooms have one or fewer particles per 0.5 micrometer cubed area. Class 10 cleanrooms have 10 or fewer particles per 0.5 micrometer cubed area. Ascending class grades rise by a factor of 10.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Because people often work in cleanrooms, they are required to follow dress and behavior guidelines to limit the amount of particles they will bring into a cleanroom or particles they will shed while working in the environment. Workers must change from street clothes into specially designed outfits, often with full hood coverings, gloves, and breathing masks. Workers must also enter through an air shower to eliminate remaining particles on the cleanroom suit, and then pass items into the cleanroom through a small chamber that prevents outside air from entering the clean environment.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><b style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanroom Air Filtration</b></span></span><b style="background: transparent; border: 0px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><o:p></o:p></b><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Cleanrooms employ air filtration to limit the particles in the environment air. Typically, this is through the use of either a highly efficient particulate air (HEPA) or ultra low particulate air (ULPA) filter. These filters can remove roughly 99.9 percent of all microparticles in room air by applying either laminar air flow or turbulent air flow techniques to the environment air.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Laminar air flow refers to air that flows in a straight, unimpeded path. Unidirectional flow is maintained in cleanrooms through the use of laminar air flow hoods that direct air jets downward in a straight path, as well as cleanroom architecture that ensures turbulence is lessened. Laminar air flow utilizes HEPA filters to filter and clean all air entering the environment. Laminar filters are often composed of stainless steel or other non-shed materials to ensure the amount of particles that enter the facility remains low. These filters usually compose roughly 80 percent of the ceiling space. Cleanrooms employing laminar air flow are typically referred to as Unidirectional Airflow Cleanrooms.</span></span><o:p><span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><br /></span></span></o:p></div>
<div style="background: rgb(255, 255, 255); border: 0px; color: #363636; font-family: arial, helvetica, sans-serif; font-size: 13px; margin-bottom: 1em; margin-top: 1em; outline: 0px; padding: 0px; vertical-align: baseline;">
<span style="background: transparent; border: 0px; font-size: small; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><span style="background: transparent; border: 0px; font-family: Georgia; font-size: 16px; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Non-unindirectional airflow cleanrooms utilize turbulent airflow systems to clean particulate air and maintain a clean environment. While laminar air flow filters are often a component of turbulent airflow systems, they are not the only systems employed. The entire enclosure is designed to use laminar flow and random, non-specific velocity filters to keep the air particle-free. Turbulent airflow can cause particle movement that can be difficult to separate from the rest of the air, but non-unidirectional airflow systems count on this random movement to move particles from the air through the filter.</span></span></div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-23865876587165326632016-03-22T10:59:00.001-07:002016-03-22T10:59:30.035-07:00Contamination Control and Environmental Monitoring of GMP QC Cell-Based Bioassay Laboratories<div style="background-color: white; border: 0px; color: #333333; font-family: 'lucida sans', sans-serif; font-size: 13px; line-height: 1.75em; margin-bottom: 1.5em; margin-top: 0.25em; outline: 0px; padding: 0px; vertical-align: baseline;">
Biotherapeutic medicines generated by living cells or organisms are larger and more complex than chemically synthesized, small molecule medicines and feature varied mechanisms of action (MOA). They also are more prone to heterogeneity, and subtle differences may occur across product lots, resulting from differences in conditions used in their production processes, including variables such as differences in cellular post-translational modification, cell passage and culture, production and purification.</div>
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Good manufacturing practices (GMP) quality control (QC) <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">in vitro</em> potency assays are required for the release of biotherapeutics, applied to demonstrate product performance consistency across lots and time. Bioassays often apply primary or clonal cells cultured under conditions that support modeling of the drug product’s cellular MOA, and often employ complex methods with multiple factors (product, cells, etc.) that influence variability and require highly trained scientists and analysts. To address this, guidance documents support the generation and validation of robust methods based upon a principle of relative potency (USP <111>, Chapters 1032, 1033 and 1034). Assay and test sample acceptance criterion are strictly set to identify good and bad assays and products, relative to method validation limits and characterized biotherapeutic reference standards.</111></div>
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Cells used are cultured via standard techniques, and bioassays are frequently performed without antibiotics because of the potential to affect product-specific responses. Microbial contamination also would alter the cell responses elicited, so successful validation and performance of these bioassays require they be performed by highly trained personnel in laboratories designed, equipped and controlled to prevent culture contamination. Integral to this process is having an effective contamination control (CC) program with analysts trained in the application of aseptic technique (Fresney, Basic Principles of Cell Culture; <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Culture of Cells for Tissue Engineering</em>, Ch. 1 eds., John Wiley & Sons, Hoboken, NJ, 2006; and Phelan, Basic Techniques in Mammalian Cell Tissue Culture,<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Curr. Protoc. Cell Biol</em>. 1.1.1 - 1.1.18, September 2007).</div>
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GMP QC cell-based bioassay laboratories (QC bio assay labs) do not perform aseptic manufacturing, but, for the reasons described above and because there are no regulations specific to their function, ISO 14644 (class 8), U.S. Food and Drug Administration (FDA) Sterile Drug Products Guidance (2004) and USP <1116>(controlled support), and Eudralex Volume 4 Annex 1 (grade D) manufacturing cleanroom recommendations/requirements are applied. The directives include appropriate design, engineering and process control infrastructure, validated CC and environmental monitoring (EM) programs to ensure both viable (<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Table 1</em>) and non-viable particulate contamination limits are met, but are intended for facilities that <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">support</em> aseptic manufacturing processes. They greatly exceed the principles generally applied to cell and tissue culture.</1116></div>
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Table 1. Regulation or Recommendations for Microbiological "In Operation" cfu Limits</h5>
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Eudralex Vol. 4 An. 1 (15) directs that grade C and D monitoring “in operation should be based upon the principles of quality risk management.” The “requirements and action/alert limits will depend on the nature of the operations carried out.” While still directed at aseptic manufacturing and support operations, the only defined requirement (18) is that “monitoring should be frequent.” While some flexibility is generally expected and allowed in the recommendations/requirements for measures applied to such classified facilities, only current USP <1116> (38-NF33, 2015) cleanroom guidance suggests that non-sterile applications (such as QC bioassay labs) require different microbial control strategies. In addition, the current USP <1116> has recommended that, rather than defined microbial limits, sampling should be directed toward determination of contamination rates (<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Table 2</em>) as a better estimation of CC program effectiveness. This is based upon acknowledgement that even ideal cleanroom design and operations <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">cannot prevent all contamination</em>, the source of which is invariably human operators. Expectations for establishing and maintaining a “sterile” environment are recognized in that document to be "technically not possible and unrealistic.” As these, too, are directed toward aseptic manufacturing and processing facilities, this can and does leave application of CC and EM method requirements subject to the interpretation of individual laboratories and regulatory agencies.</1116></1116></div>
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Table 2. USP <1116> Recommended Contamination EM Frequency and Incidence Rate Limits</1116></h5>
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PPD<span style="border: 0px; bottom: 0.4em; font-family: inherit; font-size: smaller; font-style: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">®</span> Laboratories performs GMP QC bioassay testing in three GMPcompliant laboratories in the U.S. and Ireland. All are designed, built, controlled and monitored to comply with the aseptic manufacturing cleanroom <strong style="border: 0px; font-family: inherit; font-style: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">controlled support</strong> requirements, and extending aseptic cell culture practices beyond those generally recommended (<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Table 3</em>). PPD’s first QC bioassay lab (B5-156) was commissioned for GMP testing in 2008 at the site in Middleton, Wisconsin, U.S. It consists of a single, 750 ft<span style="border: 0px; bottom: 0.4em; font-family: inherit; font-size: smaller; font-style: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">2</span> controlled access lab with an exterior gowning/degowning room and operational workflow designed to support the validated CC program. Every biosafety cabinet (BSC) testing event currently includes non-viable particulate and viable settle plate EM. This is supplemented by limited weekly cleaning and EM sampling in BSCs and general lab areas; along with complete monthly cleaning, with full post-cleaning EM in BSCs and pre-and post EM for general lab areas. EM for mycoplasma contamination is performed quarterly. Results from EM are reported semi-annually, and, since implementation, no contamination trends nor any mycoplasma have been detected. There have been only four documented culture contamination events (none impacting QC testing, and none affecting cell bank generation) since recordkeeping was initiated in March 2012, while none have occurred since April 2013.</div>
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Table 3. PPD applied CC practices, compared with those described for basic aseptic cell culture principles (italics denote measures not described in basic principles)</h5>
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In May 2013, PPD commissioned a second 6,200 ft<span style="border: 0px; bottom: 0.4em; font-family: inherit; font-size: smaller; font-style: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">2</span> controlled access lab suite (B8) in Middleton (GMP certification provided July 2015). A third lab, at PPD’s Athlone, Ireland, GMP facility (Athlone lab) was commissioned in October 2014, and added another 2,000 ft<span style="border: 0px; bottom: 0.4em; font-family: inherit; font-size: smaller; font-style: inherit; font-weight: inherit; line-height: inherit; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">2</span> of bioassay testing labs to support EU GMP biotherapeutic testing (GMP certification provided January 2015). The design and materials of both suites were based upon B5-156, with controlled workflow and identical CC programs. However, because of the demonstrated effectiveness of the B5-156 program, EM was reduced to complete quarterly pre- and post-cleaning EM in the culture laboratory, and annual pre-and postcleaning EM in the rest of the suite (settle plates were added to the quarterly Athlone bioassay lab EM).</div>
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For the B8 site, EM reports are prepared annually, and no significant EM trends or mycoplasma have been detected since initiation of operations. In that laboratory suite, 16 culture contamination events were recorded since commissioning, and increased in frequency from July to September 2014. These did not correlate with an EM viable trending increase, and none impacted the generation of cell banks. In one case, culture contamination resulted in a three-day delay in testing a QC stability sample. As for the B5-156 laboratory, all culture contaminants were identified for genus and species, and all were associated with aquatic environments (all various species of Brevundimonas, Burkholderia, Methylobacterium and Ralstonia).</div>
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An investigation into the observed increase in culture contamination events for causes determined the following: 1) the water baths used to warm media and reagents were the likely contamination source; 2) during this period the required cleaning and EM were not being performed per SOPs; 3) increased staffing had doubled lab activities; and 4) cell culture/aseptic technique training of new employees varied by trainer. (Note: Half of the events were associated with training.)</div>
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Corrective action responses included: 1) changing the water bath microbicide; 2) retraining of cleaning/EM personnel and boosting EM oversight to ensure compliance; and 3) standardizing cell culture/ aseptic technique training. Since implementation in October 2014, there have been no instances of culture contamination in the laboratory (last event recorded was September 23, 2014).</div>
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To demonstrate that the Athlone lab’s application of the U.S. PPD CC and EM programs provided “adequate assurance of control in the environment” compared to other PPD labs performing the same function, a temporary (six month) increase in the EM program (above that applied in the B5-156 lab, with each analyst also performing weekly in-use viable air, surface, equipment and glove EM) was implemented. Prior to the conclusion of that study, the PPD Middleton B8 QC culture laboratory increased gowning (to apply disposable, whole body lab suits and boot covers); performed validation of disinfectant effectiveness and added sporocide to BSC material decontamination; and increased EM to a monthly culture lab frequency (quarterly for support areas) and weekly in-use viable monitoring (as applied temporarily in the Athlone lab). These activities have required a substantial increase in support staffing and have increased analyst time required to perform cell culture by approximately 20%.</div>
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Results generated from the Athlone lab six-month increased EM evaluation period (using the original CC program copied from the U.S. sites) and from the first three months of increased B8 culture lab BSC EM confirmed a lack of laboratory and in-use BSC sterility. At both sites, and across 32 analysts and almost 500 cell culture EM events, there was viable contamination observed (<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Tables 4 and 5</em>), but no mycoplasma was detected. Viable contaminant levels were observed, but no coincidental excursions from PPD’s action/alert limits occurred and only three analyst glove contaminations occurred consecutively across EM events. Over this period, no EM trends were observed, and, in all but four instances (<1 5="" 90="" 93="" all="" and="" aseptic="" athlone="" b8="" b="" bscs="" but="" cfu="" class="" cleanliness="" cleanroom="" colony="" contamination="" controlled="" d="" em-detected="" em="" established="" eu="" events="" facilities.="" fda="" floors="" for="" forming="" grade="" in="" levels="" limits="" m3="" manufacturing="" met="" microbiological="" of="" operation="" outside="" p="" particulate="" processing="" respectively="" source="" support="" targets.="" the="" units="" were="" within=""><div class="smallImage center imageCaption center zoomImage" style="background-color: white; border: 1px solid rgb(204, 204, 204); color: #333333; display: table; font-family: 'lucida sans', sans-serif; font-size: 13px; line-height: 19.5px; margin: 10px auto; outline: 0px; padding: 5px; vertical-align: baseline; width: 586px;">
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Table 4. PPD B8 Oct-Dec 2015 (Culture Lab only) and Athlone Jan-Jun 2015 Laboratory Contamination Load (high cfu/site)</h5>
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Table 5. PPD B8 Oct-Dec 2015 (Culture Lab only) and Athlone Jan-Jun 2015 and Laboratory Percent Contamination Frequency</h5>
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Assessing the increased facility CC and/or EM results based upon USP <1116> contamination frequency guidelines demonstrated that the QC labs’ BSCs met controlled support manufacturing cleanroom contamination frequency limits across the respective periods (Table 5), while the lab areas in Athlone did not. The EM results in Athlone and B8 demonstrated that cleaning procedures reduced, but did not eliminate, contamination events.</1116></div>
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During the first three months after the increased BSC CC and EM were implemented, B8 EM observations did show reduced BSC contamination incidence and frequency compared to the Athlone EM during the sixmonth period that the original CC program was applied. However, the B8 settle plate results were similar to historical data collected in the B5-156 cell lab. There also was no indication that the extra CC measures had any impact on glove contamination, when comparing the Athlone and B8 EM results. In addition, the B8 culture lab EM, applying an unchanged CC program outside the BSCs, had ~50% of the observed EM contamination frequency as the Athlone lab.</div>
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Despite these EM results and since measures were implemented in the U.S. cell labs after introduction of corrective active measures following the September 2014 internal investigation, zero cell culture contamination events have been recorded at any PPD GMP QC bioassay laboratory.</div>
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Conclusions</h3>
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GMP QC bioassay labs <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-style: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">do not</strong></em>perform<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"> aseptic manufacturing/processing</em>. However, efficient generation of cell cultures and banks to support such testing does require that effective CC (that incudes analyst training in aseptic technique) and EM programs be implemented to establish and maintain a sufficiently clean environment to support these activities. Another valuable indicator of CC program effectiveness is recording culture contamination events, as these can help establish frequency and identify patterns that might be indicators of a lack of appropriate CC.</div>
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CC program effectiveness also can be monitored by a bioassay’s failure rate. The complex and variable nature of these methods requires establishing validated system suitability specifications so as to enable detection of good and bad assays, as well as product. Contamination of cells can and does alter activity and result in assay failure. Repeated assay failures - triggering GMP quality investigations - can support identification of CC system failures.</div>
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It is estimated that at least 6,500 GMP QC sample tests have been performed and at least 100 cell banks generated since the initiation of culture contamination records (March 2012). While it is possible that cell culture contamination has resulted in assay failures, none have ever been recorded as a demonstrated cause within PPD’s QC bioassay labs. During this period, PPD’s QC bioassay labs have recorded 20 culture contamination events, all with organism identification related to aquatic environments. As noted previously, half were linked to a failure to follow cleaning and EM procedures over a three-month period and half occurred during analyst training, while none have been recorded since corrections were implemented in October 2014.</div>
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Throughout the service history of the PPD QC bioassay labs, application of validated CC measures (that includes recording of culture contamination events and monitoring of assay performance) and EM programs has demonstrated program efficacy equivalence to aseptic manufacturing <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">controlled support</em> cleanroom expectations, with no significant EM trending across sites and time. While culture contamination events have been recorded, only one has had an impact on GMP QC bioassay sample testing (resulting in a stability sample testing window being missed by three days) over a multi-year period.</div>
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The results of added EM testing at two sites over a three- and sixmonth period <strong style="border: 0px; font-family: inherit; font-style: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">fail to link BSC in-use contamination with culture contamination events</em></strong>, supporting B8 observations in which routine EM did not trend with increased culture contamination events. Further, increased CC measures for that site did not decrease observed glove contamination event frequency, relative to the original CC program, when comparing the EM between the two sites. The increased CC had no impact on culture contamination, but, regardless of the CC program applied, no culture contamination was observed in either laboratory.</div>
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It is possible to conclude that, with PPD’s original CC program and its highly trained staff, a reduced EM plan (that includes reporting and assessment of culture contamination and linked assay failure events) is adequate to ensure proper cleaning/disinfection is reducing contamination to a level that allows for effective GMP QC bioassay testing.</div>
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In summary, it is appropriate that, in the absence of specific regulations, QC bioassay labs follow available aseptic manufacturingcontrolled support regulations and <em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">appropriate application of quality risk management</em> supported by facility performance histories, as directed by Eudralex Vol. 4 An. 1 (15). However, as our results clearly demonstrate, GMP QC bioassay lab CC and EM programs can be effective without meeting the requirements of aseptic manufacturing core or processing cleanrooms, as their expectations for generation and maintenance of a nearly aseptic environment are required to<em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><strong style="border: 0px; font-family: inherit; font-style: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">prevent product contamination</strong></em>, while GMP QC bioassay labs need only to keep cell cultures free of microbial contaminants. PPD’s data suggest that an effective CC program that combines EM, monitoring of culture contamination frequency and organism identification, and GMP required fit-for-purpose application and monitoring of rigid and specific test method system suitability are adequate measures for such laboratories. We encourage the initiation of dialogue between industry and regulatory agencies to determine and recommend best practices, so as to reduce the current variability of CC and EM applied and expected programs.</div>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com2tag:blogger.com,1999:blog-2150866002029873548.post-51460337906777337182016-03-22T10:57:00.003-07:002016-03-22T10:57:47.322-07:00Regulatory Strategy for Long-Term Stability Conditions to Support Submission in Zone IV Countries<div class="header" style="background: white; border-bottom-color: rgb(79, 111, 24); border-bottom-width: 1px; border-style: solid none dotted; border-top-color: rgb(79, 111, 24); border-top-width: 5px; color: #333333; font-family: 'lucida sans', sans-serif; font-size: 13px; line-height: 19.5px; margin: 0px; outline: 0px; padding: 15px 0px; vertical-align: baseline;">
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Regulatory Strategy for Long-Term Stability Conditions to Support Submission in Zone IV Countries</h1>
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This paper provides a recommendation for selection of long-term stability conditions for submission of room temperature storage drug products in Zone IV countries in the face of a confusing mixture of expectations from international regulatory bodies. This confusion has resulted from multiple messages from groups such as the International Conference on Harmonization (ICH), the World Health Organization (WHO), regional associations of nations, and several individual countries themselves. The scope of this paper covers drug products currently in development as well as approved drug products which may be required to provide Zone IV stability data as a condition for registration renewal or to support post-approval changes.</div>
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Drug substances (active pharmaceutical ingredients) are not explicitly covered in this paper. However, it is worth noting that stability study conditions for API are based on the mean kinetic temperature and anticipated humidity exposure of the actual storage conditions for the API. Drug substances manufactured or used by many firms typically are not exposed to Zone IV storage temperatures for any significant period of time. Short-term exposure to local ambient conditions during the transportation period to drug product manufacturing sites can be supported by accelerated stability data packages (40ºC/75%RH).</div>
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It has long been recognized that the difference in climatic conditions in varying regions of the world need to be taken into consideration when planning stability studies to determine the shelf-lives of drugs. Grimm examined world climatic data and demonstrated the importance of taking this into account by proposing different stability conditions for different climatic zones [1,2]. Zone I was defined to Temperate, Zone II Subtropical or Mediterranean, Zone III hot and dry, and Zone IV hot and humid. This work provided a basis for the ICH to propose a unified approach among the United States, the European Union, and Japan, all in climatic Zone II, for stability studies to be performed at 25ºC/60% RH for long-term testing in 1993 [3].</div>
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Further work by the ICH Stability Working Group led to the idea of a single long-term stability condition for Zone IV countries which would also serve as an intermediate condition/alternative long-term condition for Zone II countries. Their proposal to use 30°C/65% RH as this condition was embodied in ICH Q1F, which was adopted by the ICH Steering Committee in February 2002 [4]. However, the proposal did not receive sufficient support from Zone IV countries, many of which noted that they experienced higher relative humidity than the recommended 65%.</div>
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In 2005 the ASEAN group of nations (Indonesia, Malaysia, the Philippines, Singapore, Thailand, Brunei, Burma (Myanmar), Cambodia, Laos, and Vietnam) published a draft regional stability guidance that called for long-term stability studies to be performed at 30ºC/75% RH [5]. Soon after, Brazil, which had changed its long-term stability requirement from 30ºC/70% RH to 30ºC/65% RH after the publication of ICH Q1F, changed again, this time to 30ºC/75% RH [6]. As a result, ICH withdrew the Q1F guidance in 2006 [4].</div>
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In October of 2005, the WHO took the position of creating a Zone IVa and IVb which would have long-term stability data requirements of 30ºC/65% RH and 30ºC/75% RH, respectively, and allowing each country to designate which sub-zone it was in [7]. The current WHO stability guidance has an appendix listing countries and the sub-zone they have selected [8].</div>
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In addition to requiring Zone IV stability data for registration of new drugs, a number of countries, such as Brazil, also require that firms provide Zone IV stability data for registration renewals or to support post-approval changes, even where such data was not in the original submission [6].</div>
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RECOMMENDED APPROACH FOR PROVIDING STABILITY DATA FOR ZONE IV COUNTRIES</h2>
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Since some Zone IV countries require 30ºC/75%RH stability studies while others will accept 30ºC/65%RH data, firms wishing to register their drugs globally are faced with a dilemma. It is not economically practical to perform two sets of Zone IV stability studies, one at 30ºC/65%RH and another at 30ºC/75%RH.</div>
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Therefore, we recommend that room temperature drug products to be registered in Zone IV countries be supported by:</div>
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<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">30ºC/75%RH long-term stability data on at least one package configuration for dry solid oral products.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">30ºC long-term stability data on at least one package configuration for parenteral products.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Other package configurations for solid oral products and parenterals may be tested under Zone IV conditions as above or dealt with by bracketing.</li>
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One clarification regarding point (b) above is useful to note. The exclusion of humidity in the recommended conditions for stability studies of parenterals is specific to drug products packaged in impermeable containers. The exclusion is not based on the product itself but on whether it is packaged in an impermeable container and intended for room temperature storage. The classification of packaging as moisture impermeable should be evaluated based on Moisture Vapor Transmission Rate (MVTR) data. It should be noted that glass vials with a rubber stopper are not automatically defined as impermeable by any regulatory authority. Where 30°C/75%RH data do not exist, but either 30ºC/65%RH data or 30ºC/ambient humidity data are available, it may be possible TESTINGto demonstrate that a particular vial/stopper/crimp combination is impermeable by providing actual MVTR data to the regulators.</div>
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Development teams must look carefully at early stability data and at marketing plans and decide on packaging that will provide adequate protection at 30ºC/75%RH. Packaging more protective than that used for Zone II countries may be needed. Teams will also have to determine when to begin the primary stability studies at Zone IV conditions. This timing will be a business decision based on submission plans in the Zone IV countries which require this data, therefore communication between marketing and development and Regulatory Affairs is essential.</div>
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For products marketed in Zone IV countries which require 30ºC/75% RH or 30ºC/65%RH stability data for registration renewal or to support post-approval changes, the development team should assess the available stability data. Data may have been generated at 30ºC/65%RH (per the withdrawn ICH Q1F recommendations). Many Zone IV countries will accept this data, in some cases even where 30ºC/75% RH is expected for new products. If neither 30ºC/75% RH or 30ºC/65%RH data is available, new stability studies may need to be initiated. This may mean that the product packaging has to be reevaluated, as some products that are stable at 25ºC or 30ºC at low humidity, may not be so at 30ºC/75% RH.</div>
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Table 1 - Countries Recommended for Zone II Long-Term Stability Conditions<br />A: From regional harmonization groups (e.g., ASEAN, ICH and GCC) or country regulators to WHO<br />B: From country regulators to WHO at 13th International Conference of Drug Regulatory Authorities (ICDRA),16–18 September 2008<br />C: Information provided by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) based on literature references</h5>
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The remainder of this paper includes three tables derived from the 2009 WHO stability guidance [8] covering approximately 200 countries and listing both the long-term stability conditions provided for in the WHO document and our recommended long-term stability conditions. Table 1 lists those countries for which 25ºC/60%RH is recommended in the WHO guide. Our recommendation for the countries listed in Table 1 is to use either 25ºC/60%RH or 30ºC/75%RH. If a drug product is sufficiently stable, then 30ºC/75%RH represents a single long-term stability condition TESTINGfor all global submissions. If the drug product is not sufficiently stable, then 25ºC/60%RH would be used for registration in the US, EU, and other Table 1 countries. For registration in other countries, more protective packaging or other measures to ensure stability at 30ºC/75%RH would be necessary.</div>
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Table 2 - Countries Known to Expect Zone IV Long-Term Stability Conditions<br />A: From regional harmonization groups (e.g., ASEAN, ICH and GCC) or country regulators to WHO<br />B: From country regulators to WHO at 13th International Conference of Drug Regulatory Authorities (ICDRA),16–18 September 2008</h5>
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Table 3 - Countries Estimated to Have Zone IV Climatic Conditions That Did Not Provide Specific Requirements to WHO<br />C: Information provided by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) based on literature references</h5>
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Table 2 lists those countries for which 30ºC/75%RH is recommended in the WHO document based on information taken from a regional guidance such as the ASEAN stability guidance [5] or from direct communication from a specific country’s health authorities to WHO [8]. Table 3 lists countries for which 30ºC/75%RH is recommended based on climatic information obtained by WHO from the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). For countries listed in Table 3, because WHO could not obtain a clear indication of their long-term stability requirement, it is essential to verify current expectations on a country-by-country basis for every planned regulatory document which requires stability data whether for registration, re-registration, or post-approval changes. If the current stability requirements for a country cannot be verified, then 30ºC/75% RH data requirements for countries in Table 3 must be assumed as accurate and such data provided in regulatory submissions.</div>
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In summary, this paper represents a snapshot in time with our current best understanding of expectations in approximately 200 countries; verification of a country’s regulatory expectations in respect to Zone IV stability should be considered as country expectations continue to evolve and change.</div>
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SOME COUNTRY-SPECIFIC NOTES</h2>
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<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">The entry for Canada in the WHO guidance lists the long-term stability condition as 30ºC/65%RH only [8]. This is at odds with Canada’s adoption of its own version of the ICH Q1A guidance which clearly states, “It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH [9]." Therefore we have placed Canada in Table 1.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">The entry for Iraq in the WHO guidance provides for a long-term stability condition of 30°C/35% RH [8]. This is presumably because Iraq is actually a climatic Zone III country, that is, hot and dry. Long-term stability testing at low humidity is particularly important for drugs in aqueous solution in semi-permeable containers to ensure that moisture loss from the drug product over time does not lead to excessive concentration, erroneous dosing or drug substance precipitation. Such testing is provided for in ICH Q1A [3]. If it cannot be established that the container is of sufficiently low permeability, then long-term testing at 30°C/35% RH should be considered.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">The entry for Israel in the WHO guidance provides for a long-term stability condition of 30°C/70% or 30°C/75% RH, but it is our understanding that Israeli regulators consider it to be a Zone II country and are working with WHO to change its entry in the guidance. As noted above, regulatory expectations must be verified.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Questions frequently arise regarding the classification of Australia. As stated in the Australian Regulatory Guidelines for Prescription Medicines, Appendix 14, Australia has climatic conditions encompassing ICH Zones II-IV, and accepts data generated at stability conditions as laid out in ICH Guidelines [10]. Australia, therefore, does not require Zone IV stability data.</li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Questions also frequently arise regarding Puerto Rico. As a territory of the US with commonwealth status, Puerto Rico is subject to U.S. Federal Laws, e.g., 21CFR 276 (b)(13). “United States means the Customs territory of the United States (i.e., the 50 states, the District of Columbia, and the Commonwealth of Puerto Rico), but not the Territories." The U.S. FDA expectation of Zone II stability conditions therefore includes Puerto Rico.</li>
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CONCLUSION</h2>
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There has been a great deal of confusion about the proper choice of long-term stability conditions for various countries. This has resulted from conflicting advice from sources such as ICH and WHO that would otherwise have been expected to provide clear, scientifically based recommendations in this area. The decision of WHO to accept a mixture of 30°C ± 2°C/65% RH ± 5% RH and 30°C ± 2°C/75% RH ± 5% RH on a country-by-country basis for climatic Zone IV lead to our recommendation to select 30°C ± 2°C/75% RH ± 5% RH as a single condition to be used for all Zone IV countries since running parallel stability studies at both conditions would be prohibitively expensive. There have also been questions of how, exactly, it can be determined whether a country is a Zone IV country or not. Since the WHO has decided to let each country determine its own status without providing a clear cut set of temperature/humidity criteria to differentiate one climatic zone from another, a list of countries with assignments is needed. This paper provides such a list in Tables 1-3, basing it on the 2009 WHO stability guidance. It is important to remember, however, that the information in this paper represents the situation at the time of writing and with 200 countries to deal with, some change must be expected over time. Therefore, the recommendations provided in this paper should be verified prior to initiating stability studies.</div>
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REFERENCES</h2>
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<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Grimm, W. Drugs Made in Germany, 28, 196-202 1985.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Grimm, W. Drugs Made in Germany, 29, 39-47 1986.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">ICH Q1A (R2), Stability Testing of New Drug Substances and Products (current version 2003). http://www.ich.org/LOB/media/MEDIA419.pdf.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">ICH Q1F, Stability Data Package for Registration Applications in Climatic Zones III and IV, (published 2002, withdrawn 2006) http://www.ich.org/LOB/media/MEDIA3124.pdf.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">ASEAN Guideline On Stability Study Of Drug Product 2005.http://pharmalytik.com/images/stories/PDF/asean%20stability%20guidelines%20-%2022%20feb%202005.pdf.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Resolution No. 1 of July 29, 2005, Guide For The Undertaking Of Stability Studies, Brazil 2005.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Consultation of Stability studies in a global environment, WHO 2005. (http://www.who.int/medicines/areas/quality_safety/quality_assurance/ConsultStabstudies/en/).</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">WHO Expert Committee on Specifications for Pharmaceutical Preparations, 43rd Report, Annex 2, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products, WHO Technical Report Series, No. 953, 2009, pages 87-127.http://www.who.int/medicines/publications/pharmprep/pdf_trs953.pdf#page=101.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Canada: Adoption of ICH Guidance: Stability Testing of New Drug Substances and Products - ICH Topic Q1A(R2), file number 03-118437-914 2003. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1a(r2)-eng.php.</em></li>
<li style="border: 0px; font-family: inherit; font-style: inherit; font-weight: inherit; line-height: 1.5em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;"><em style="border: 0px; font-family: inherit; font-weight: inherit; line-height: 1.75em; margin: 0px; outline: 0px; padding: 0px; vertical-align: baseline;">Australian Regulatory Guidelines for Prescription Medicines, Appendix 14, Stability Testing, 2004. http://www.tga.gov.au/pmeds/argpmap14.pdf.</em></li>
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Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0tag:blogger.com,1999:blog-2150866002029873548.post-59766267574566612722016-03-22T10:47:00.000-07:002016-03-22T10:47:13.610-07:00Process Validation Challenges for Technology Transfer<h2 style="background-color: white; border: 0px; color: #313131; font-family: 'lucida sans', sans-serif; font-size: 1.83333em; font-weight: normal; line-height: 1.1em; margin: 1.25em 0px 0.75em; outline: 0px; padding: 0px; text-transform: uppercase; vertical-align: baseline;">
ABSTRACT</h2>
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For a commercial technology transfer, the ultimate measure of success is regulatory approval of the transferred process at the new site. A major step in obtaining regulatory approval is the process validation package. Successful design and execution of process validation requires proactive planning for both technical as well as logistical challenges. This article will discuss some common challenges that are faced as well as strategies to overcome them.</div>
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INTRODUCTION</h2>
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Technology transfers inherently involve a number of technical as well as logistical challenges.</div>
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Overcoming these challenges successfully within project timelines requires careful planning. One major activity in technology transfer and licensure of the process at the new facility is the process validation which demonstrates that the new facility delivers product of comparable quality with consistent performance. Considerations and strategies to successful validation of a transferred process are discussed here.</div>
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FACILITY FIT ASSESSMENT</h2>
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One of the first challenges to overcome in transferring a manufacturing process is to fit the process into the target facility. In the initial stages of the technology transfer, a comprehensive review of process requirements and comparison with facility capabilities should be performed. A thorough fit assessment up front can help avoid unexpected delays or hidden costs later. Common examples of process requirements to evaluate include the expected titer/scale for the process against available column sizes and loading densities; comparison of expected flow rates and pressures against equipment ranges; evaluation of expected product pool sizes against tank storage capacities and effective mixing ranges; review of process temperature ranges against equipment temperature control capability; and review of chemicals used in the process for any impacts on waste limits or chemical storage permits. Local regulations on discharge limits can vary widely, and care should be taken to ensure that the assessment is performed against the applicable regulations for the target site.</div>
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Any changes to the process to accommodate the facility fit may result in additional process validation requirements. Changes should be minimized as practically feasible, utilizing the same scale and equipment as the original site when possible. When scaling up to a larger facility, maintaining the same scale factor across the entire process train should be targeted. Practically, there will always be some differences between facilities. A remediation plan for any potential gaps should be prepared, along with a risk assessment of any potential changes or differences. Gaps can be addressed either by facility modifications, which may entail capital investment, or by changes to the process itself, which may require process validation or characterization to support. While an upfront capital investment may seem undesirable, the time and resources required for the additional validation activities should also be considered. The decision should also factor in the criticality or impact of the step on product quality. Minimizing process changes minimizes risk of unintended differences in process performance and product quality, and may also facilitate regulatory approval for the transfer.</div>
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DOCUMENTATION</h2>
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Once the process fit into the facility is defined, a site-specific process description and process flow diagram help to document and communicate the implementation plan across the various functional groups involved in the transfer (e.g., Engineering, Manufacturing, Process Development, Quality, Regulatory). Highlighting facility differences or process changes between the originating site and the receiving site in these documents will also facilitate assembly of a process validation project plan. The process validation project plan should include not only those additional studies required to support process changes, but also those studies which will be used to demonstrate the comparability of the product quality and the process performance. In constructing the validation project plan, one should also consider which unit operations may require site-specific studies at full-scale even with no changes to the process. For example, differences in piping or valve configurations may need to be accounted for by full-scale validation. A risk-based approach can be used to determine and document whether a site-specific validation study is required.</div>
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Leveraging existing process validation studies can help to streamline the validation plan, but the rationale for the applicability of those previous studies to the transfer at hand should be clearly documented. In projects where timelines are critical or constrained, making use of document templates can prove effective. Templates can help to provide consistency as well as limit the amount of review required in later phases of the project when technical resources are needed for other activities associated with the process transfer. The templates can undergo initial review with placeholders for missing details, followed by a final review with the data once available. However, this approach also requires careful document management and project management to ensure critical information receives the appropriate review once populated. For example, drafting of regulatory submissions may begin prior to completion of all process validation and characterization studies. Final review of the submission should ensure that all stated process parameter ranges match the ranges supported by the validation.</div>
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PROCESS SAMPLES</h2>
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Process validation activities require many manufacturing process samples beyond those typically needed for QC in-process and release testing. To ensure that all the samples needed to support validation are acquired during the manufacturing campaign, a comprehensive sampling plan should be developed. The sampling plan should include a list of samples required to support process validation activities, as well as details on sample container types, storage temperature requirements, the analytical testing to be performed for each sample, and the testing timeline. If the samples will require shipment, one must also consider what additional materials are required for shipment – for example, shipping containers, temperature monitoring devices, and documentation for chain of custody. Seemingly simple decisions such as container type can often have a big impact. For samples which will be stored frozen, the physical properties of the container material should be evaluated to ensure that the container will not become fragile or brittle at the intended storage temperature. For samples which will be shipped on dry ice, the gas permeability of the container should also be evaluated. Higher gas permeability may result in changes to the sample pH due to diffusion of carbon dioxide.</div>
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In addition to the samples required to support process validation studies, additional samples may also be desired for potential troubleshooting activities. For example, a sample of manufacturing feedstock can be processed in a lab-scale model to help determine if unexpected issues seen at full-scale are feedstock-related or facility-related. Having a lab-scale model available in which studies can be run in real-time, or as close to manufacturing production as possible, can be useful in such cases.</div>
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RESOURCES AND RESPONSIBILITIES</h2>
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It is also critical to identify and gain agreement on who will execute the outlined studies, as well as a timeline for the activities involved. In the 2011case of process validation studies, these activities include who will author the protocol, obtain the samples, deliver samples, perform analytical testing, and prepare the summary report. The roles and responsibilities should be clearly defined for all activities. Technology transfers are inherently multi-functional projects involving more than one site, and one site may assume an activity is the responsibility of the other. Defining all activities up front ensures an activity is not overlooked later. Similarly, expected lead times should be reviewed and documented, as lead times for an activity may be different from site-to-site. Availability of raw materials or consumables, shift coverage, and analytical testing lead times are all examples of activities which should be examined for differences between sites. Close coordination and communication between all the resources involved is critical, as timelines often can shift during the course of the project.</div>
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LOGISTICAL CONSIDERATIONS FOR INTERNATIONAL TRANSFERS</h2>
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Additional challenges are faced when the technology transfer is to a facility in a different country than the originating site. There are the additional communication challenges of a different culture, different language, and/or different time zone. Even in instances where English is spoken proficiently by all team members as the common language, different cultural influences can result in different interpretations for a given word or phrase. While technological networking advancements have made it far easier to hold teleconference meetings while viewing a common presentation in real-time, occasional face-to-face meetings are still invaluable in establishing relationships and developing an innate understanding of each team member’s communication style.</div>
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CONCLUSIONS</h2>
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Technology transfers are highly complex, multi-functional projects, but anticipation of the challenges can help ensure success. Careful evaluation of the process fit with the facility and minimizing changes; clear documentation of the process and project plan; defined roles, responsibilities, and timelines; and an appreciation for cultural differences between originating and receiving sites are all considerations that, when accounted for up front, can help to ensure a successful technology transfer and validation</div>
Niazihttp://www.blogger.com/profile/08621833844620878446noreply@blogger.com0