Barrier Isolators and Microenvironments for Cleanroom Applications

Source: Absolute Control Systems

Introduction 
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.

Definitions
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.

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.

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.

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.

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.

Advantages
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.

Small scale cleanroom
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.

Cleanable Zone of Concern
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.

Plan ahead
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.

Operator Protection
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.

People are Dirty
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.

Superior Environment Control
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="">

What to Expect
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.

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.

Intangibles
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.

Competition and Regulation
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.

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.

Safety is Important
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.

Do I need One? 
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.

Product properties that may indicate the need for isolation / containment.

• Flammability
• Nuisance dust
• Explosive dust hazard
• Corrosive properties
• Irritants
• Allergens
• Sensitizing agents
• Toxins
• Carcinogens
• Mutagens
• Biohazards
• Low bioburden
• Germ free
• Live virus
• Visual hazard - laser
• Physical hazard - moving components
• Volatile Organic Compounds (VOC) - Emissive agents
• Sterilants
• Extreme Absolute environment - vacuum, pressure, temperature, moisture
• ULPA class environment
• Anaerobic
• Unique inert gas backgrounds
• Cross contamination between products
• Precision cleaning - microcontamination

Summary
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.

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.

Sterility Testing: Beware of the Pitfalls

By Martin Spalding, Jr., Northview Laboratories

Contents
Introduction
The Fundamental Limitation
Protecting the Integrity of the Process
Causes of True Positives
Limitations of Testing Defined
Are Isolators the Answer?
Dealing with Sterility Test Positives
References

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Introduction (Back to Top)

"We have a failure on your sterility test."

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.

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.

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.

The Fundamental Limitation (Back to Top)
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.

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 >1014 living bacteria cells, 1012 of these residing on the skin and 1010 in the mouth.1 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.

Protecting the Integrity of the Process (Back to Top)
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 not 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.

Swipe testing is a first-line defense against microbial contamination, but swiping only tells you after the fact if your process is contaminated.

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.

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.

Causes of True Positives (Back to Top)
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.

Limitations of Testing Defined (Back to Top)
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 10-3 for the sterility testing process. This means that for every 1000 samples tested, one false positive will occur.

This 10-3 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 10-3 level typical for pharmaceutical products.

Are Isolators the Answer? (Back to Top)
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.

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.

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.

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.

Dealing with Sterility Test Positives (Back to Top)
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.

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.

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!

References (Back to Top)

1. William Hyde, PDA Journal of Science and Technology, "Origin of Bacteria in the Clean Room and Their Growth Requirements", July/August 1998, Volume 52, Number 4, p. 154.
2. USP 23, <1211> Sterilization and Sterility Assurance, p. 1980.
3. Hank Rahe, American Pharmaceutical Review, "Implementing a Cost Effective Sterility Testing Isolator Project, Volume 1, Issue 1, 1998, pp. 34–41.

Hydroxytyrosol augments the redox status of high fat diet-fed rats

Abstract

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.

Public heath bodies should actively discourage the adoption of obesogenic high-fat diets, but HT as supplement modulates some of their harmful effects.

Role of long-chain omega-3 fatty acids in psychiatric practice

Abstract

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.

Opioid Poisonings Rise Sharply Among Toddlers and Teenagers

By DONNA DE LA CRUZOCT. 31, 2016

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CreditStuart Bradford

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.

The study, published Monday in JAMA Pediatrics, analyzed data from the Kids’ Inpatient Database, 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.

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.

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.

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 259 million prescriptions for opioid painkillers.

“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.”

Dr. Gaither said the pills should be more securely packaged and better labeled.

“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.

In a C. S. Mott poll 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.

“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.”

Jen Simon, a freelance writer in the New York City area who has writtenabout 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.

“And my doctors know I have young children — they have been to my medical appointments with me,” Ms. Simon said.

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.

“Opioids can be a ticking time bomb in your medicine cabinet,” Dr. Rosenthal said, adding that overprescribing of medications must also be addressed.

“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.”

Two Drugs for Adult Migraines May Not Help Children

By CATHERINE SAINT LOUISOCT. 27, 2016

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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. CreditCarolyn A. McKeone/Science Source

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 The New England Journal of Medicine.

Researchers stopped the large trial early, saying the evidence was clear even though the drugs — the antidepressant amitriptyline and the epilepsy drug topiramate — had been shown to prevent migraines in adults.

“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 Headache Center at Cincinnati Children’s Hospital Medical Center.

A migraine is a neurological illness characterized by pulsating headachepain, sometimes accompanied by nausea, vomiting and sensitivity to light and noise.

It’s a common childhood condition. Up to 11 percent of 7- to 11-year-olds and 23 percent of 15-year-olds have migraines.

At 31 sites nationwide, 328 migraine 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.

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.

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.

One child on topiramate attempted suicide. Three taking amitriptyline had mood changes; one told his mother he wanted to hurt himself, while another wrote suicide notes at school and was hospitalized.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.

Because of the side effects, Dr. Powers and his colleagues questioned whether the benefits of either drug outweighed its risks.

In 2014, the Food and Drug Administration approved topiramate 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.

Other experts were not yet ready to give up on drug treatment.

“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.

“I’ll simply say, ‘We have data in adults that it’s effective, but less convincing data in children and adolescents.’”

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 American Academy of Neurology.

A team of physicians, including Dr. Gloss, is revising the academy’s guidelines on pediatric migraines and planning to assess nondrug approaches.

A trial published 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.

Correction: October 28, 2016 

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.

How Technology is Disrupting Medical Device Manufacturing

Medical device sales are booming, driven by technological advances 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 trend toward the integration 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.

Robotics

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 $22 billion by 2019. 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.

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 multi-tasking robots useful for assembling hard-to-handle components, accelerating production and cutting costs.

Materials Science

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 asynthetic biomaterial that can prevent the body from rejecting implanted objects.

3-D Printing

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 Apple Rubber uses 3-D printing to manufacture a selection of over 7,000 customized medical o-rings.

Rapid Prototyping

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.

Cloud Technology

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 remotely share images 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.

Mass Measurement Precision of Small Objects in Pharmaceutical Production

Unlocking the regulations-related advantages when using the new generation of contactless measurement systems

By Arek Druzdzel and Arne Wieneke, Aiger Group AG, Zug, Switzerland

Jul 25, 2016

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.

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.

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.

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.

Mass-reading error is caused by variation in the gravitational acceleration and the resulting gravity force (weight) that are not constant around the world.

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.

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%.

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]. 

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.

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.

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.”

Removing gravity and ambience from the equation

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.

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.

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.

A new industrial application

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.

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.

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.

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.

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.

References

1. Kilogram – the base unit of mass, Wikipedia
2. Earth’s rotation, Wikipedia
3. Patent application GB2512026A
4. Pharmacopeia USP General Chapter 41 and 1251
5. European directive 2009/23/EC