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C.R. Bard Acquires SenoRx

"Our agreement with Bard represents an attractive valuation for SenoRx shareholders, and as an all cash offer, provides liquidity for shareholders," says John Buhler, SenoRx's president and CEO. "We believe the merger represents a great opportunity for the combined companies to create product leadership by offering a broader range of high-quality breast care products to our customers."

Get with the Program

During the packaging validation process, one of the tests that must be performed is a peel test. 
Images courtesy of MICROTEST LABORATORIES.

This article provides insight into the general requirements in a microbiological and physical testing program. It discusses how combination products pose a unique set of challenges to package validation engineers. For example, one key issue involves the requirement for a pharmaceutical or biologic component to meet International Conference on Harmonization (ICH) guidelines for stability in a flexible pouch under normal conditions.2 The United States Pharmacopeia (USP) provides information about ambient storage conditions of storage and shipment. 
 
Unfortunately, medical device package testing is not standardized in terms of shelf life requirements because the variation of device materials requires the manufacturer to modify ASTM conditions to bracket shipment, storage, and use conditions. FDA has yet to support and standardize an accelerated aging program and microbiological procedures. Physical testing is probably the best indicator of adequate sealing parameters. However, these tests do not give technicians the ability to extrapolate to real world microbiological ingress limits. These limits may have little benefit to the medical device manufacturer. This article discusses some of the options for testing. 
 
The Challenges of Packaging Validation
All medical device materials and drug products have a finite life span. Materials such as plastics, adhesives, polymers, and films degrade with time. Most medical devices have a primary and a secondary packaging system. Both packaging systems require validation programs. Historically, medical devices have been tested for degradation (forced degradation studies) by heating in a hot air oven at 55° to 60°C from weeks to months. This procedure, generally called accelerated aging, is based on the following formula (Q 10 coefficient): a 10°C rise in temperature doubles the chemical reaction rate. Extrapolating the rate to time gives a set point that can be used to indicate aging at room temperature and in real time. 
 
After treatment, the devices are tested for various material characteristics. These characteristics include ASTM D2240 durometer, form, fit, and function. The testing of plastics can require infrared scans, gel permeation chromatography (GPC), and gas chromatograph/mass spectrometry (GC/MS) testing for leachates. Typically, the validation program will cull out tertiary testing based on a suitable product risk analysis. Tertiary or release testing programs are typically added after the validation program to determine which analytical procedures would be required for product release.
 
Combinatory products require strict adherence to ICH guidelines for stability of the drug and biologic throughout the shelf life of the product. For products that have a delivery system (such as needleless injection systems), storage and shipping parameters are critical to maintaining required potency. For other products that have a drug coating or scaffolding application, the validation program requires a unique perspective into both medical device shelf-life studies and the ability of the drug and biologic formulation to maintain stability throughout all phases of the manufacturing and sterilization process. Formulation issues are very important prior to FDA filings, and these considerations will be a major portion of the final regulatory filing. It is important to note that this article does not address formulation. 
 
Medical device packaging validations are performed with baseline products that have not been subjected to normal warehouse storage. Nonsterile samples are required for initial fingerprint seal analysis. These data give essential background seal analysis information that is essential for comparison studies on sterile packaging. These samples reveal data changes with sterilization. All sterile samples sent in for package seal analysis measurements allow the tester to determine physical seal changes during accelerated or real-time aging studies. Transportation samples are taken from both real-time and aged products. 
 
Packaging testing guidelines are listed in ISO 11607. This document describes the available ASTM packaging tests. It also brings together many other key aspects of packaging validation (i.e., material qualification, validation of seal process, and whole package seal integrity). However, it does fall short in not speaking to a definitive validation regimen for all to follow. Physical tests that are performed may include burst, creep, creep to fail, peel, and leak. Packaging validation specialists can help manufacturers choose the most appropriate tests based on its packaging materials (see Table I). 
 
A robust packaging validation program should include transportation simulation testing with concomitant sterility testing.3 Some device manufacturers bracket the potential storage and shipment temperatures and conditions (such as air cargo) during their initial studies. The steps in the packaging validation process include the following: 
 
  • Select appropriate package material and design, qualify equipment, validate sealing process, and produce test samples. 
  • Perform burst test and peel strength creep testing on both sterile and nonsterile, nonaccelerated aged product.
  • Place an appropriate number of samples into accelerated aging for the required period. 
  • After aging, the packaging is tested for physical testing. Device samples are tested for material problems and whether or not they meet product specifications. 
  • A portion of the accelerated samples are culled for transportation simulation tests, including International Safe Transit Association and ASTM shipping tests. 
  • Packaging samples are tested for physical parameters as above. A visual exam is performed to look for holes caused by vibration testing. Device samples are tested for specification requirements. 
 
Combination products require a second-tier approach to package validation. Appropriate prevalidation questions may contain concerns over active pharmaceutical ingredient potency; biologic activity; medical device polymer, drug, and biologics interactions; and ICH stability issues.4
 
FDA has also published a guidance document titled Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products. The guidance was prepared by representatives from CDRH, the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, and the Center for Veterinary Medicine. 
 
Drug and biologic interactions with polymers can be an issue with respect to emitted dose and stability. Some medical device polymers may cause changes to small and large molecules. These changes, such as emitted dose variabilities during product use, can be critical to product launch. The testing regimen must flush out the variables for stability and concentrate on the criticality of the studies and assays in terms of experimental design and robust method development studies. Some of these issues become prominent during production scale up. 
 
Cell therapy products such as xenografts, allografts, and stem cell products create unusual challenges for the package validation engineer and FDA offers very little guidance on these issues. Cells must be able to withstand shipment and storage during a finite and defined period. Evaluation of cell lines and tissue implants during a stability program is required prior to FDA submission. There are several points to consider during package validation studies for cell therapy products, including: 
 
  • Bacterial, fungal, and mycoplasma sterility testing (USP sterility and FDA mycoplasma test).
  • Viral sterility test (FDA virus assay). 
  • Particulate test (USP).
  • Cytotoxicity (USP).
  • Container integrity testing (MBD immersion test).
  • pH analysis.
  • Buffering capacity (container) USP.
  • Leachate testing (container) GC/MS analysis.
Conclusion 
Medical device stability package validation programs should be designed to encompass the overt product storage and shipment conditions. Performing accelerated aging studies does little to address damage during shipment and storage. Damage can be caused by many factors such as aberrant conditions, stress, and overt handling, to name a few. In the future, FDA may require companies to perform similar ICH-type stability studies. In the 1991 FDA guidance document, Shelf Life of Medical Devices, by Geoffrey Clark, much needed guidance was posited. Today, however, new guidance documents are needed to address combination products and to move the medical device industry closer to ICH compliance. 
 
The necessity to develop a robust packaging validation regimen cannot be overstated. A comprehensive regulatory approach to validation during early product development can save many weeks of redevelopment and testing activities. Ideally, as FDA and the global community move toward harmonization, a stability guideline for combination products would emerge and provide a path forward for validation specialists. Combination product GMPs are also in the final review process.5 These GMPs will be the first step toward compliance issues and clarity.
 
In conclusion, all device and combination product manufacturers are required to have a robust package validation program. The testing that was presented in this article is not all encompassing. It is presented to give one a starting point for package validation programs. 
 
References
1. M Sherman, Medical Device Packaging Handbook (New York, CRC Press, 1998).
2. USP Volume 32, Section 1079, “Good Storage and Shipping Practices: Statements/Labeling of the Immediate Containers or Package Insert” (Rockville, MD) 540-541.
3. Test Series, The International Safe Transit Association, available from Internet: www.ista.org.
4. S Richter, “Combinatory Products: Navigating Two FDA Quality Systems,” available from Internet: www.microtestlabs.com/combinationpaper.
5. Federal Register 74, FR: 48423, September 23, 2009.
 
Steven Richter, PhD, is founder, president, and chief scientific officer of Microtest Laboratories Inc. (Agawam, MA).

User Tips for Cleaning and Coating Professionals

FIFO inventory control ensures the solvent is at maximum purity and ready to use when the packaging is opened.

Always think safety. Personal protective equipment such as suitable safety glasses and gloves should be specified when working with solvents. Selecting gloves for use with solvents can be complicated, because certain gloves can protect against some solvents but may be useless against others. Some gloves can be used for total immersion in a solvent, while others withstand less-permeating chemicals only with intermittent contact. Glove thickness will provide different protective factors but will also affect dexterity. Factors such as flexibility, cut, tear resistance, and temperature range should be considered. Read the product’s material safety data sheet and talk to your solvent provider to be certain that you’re using the best protective equipment for your process.

Don’t be confused by grades. Many people are confused by the terms reagent, laboratory, and technical when selecting the quality level (or grade) of a generic solvent such as isopropyl alcohol. Reagent grade is generally the highest purity available—it means the solvent is low in water content and suitable for all types of manufacturing and scientific work. This grade is often required for projects that involve living biological matter. Laboratory-grade solvents are relatively high purity, but may contain small amounts of nonvolatile residue and other impurities. They are sufficiently pure for many industrial applications but not suitable for use in food or medicine of any kind. Lastly, technical grade is a general industrial grade and these solvents may contain relatively high amounts of impurities such as water. These grades are not suitable for use in food or medicine of any kind and are usually used in low-cost industrial applications. Consider specifying reagent if you’re faced with making a choice, but uncertain on how the solvent will be used. Your supplier should be able to provide a product specification sheet to explain the differences and provide the best option.

Use weight, not volume. The best method of measuring and managing liquid inventory packaged in larger containers such as pails and drums is by weight. Liquids expand when warm and contract when cold, so issuing partial contents of a pail or drum by volume can produce significant inventory variances depending on ambient temperature. Always formulate, blend, and manage your large container liquid inventories by weight. The net weight of a liquid will remain constant regardless of ambient temperature.

Return to "No Dirty Devices Allowed".

No Dirty Devices Allowed

Many device design engineers and manufacturers do not realize the significant role that cleaning and coating methods can play in the consistency and quality of device performance once it’s in a doctor’s hands. Although it is sometimes an afterthought, cleaning and coating should be considered in every step of device design and manufacture. As an added benefit, considering these challenges in advance will ensure more flexibility in the design and manufacturing process and will ultimately support maximum profitability through low capital costs.

A vapor degreaser is part of the cleaning process for medical device cleaning and coating, especially in high volume.
Images courtesy of MICROCARE MEDICAL

 
This article discusses the top cleaning and coating challenges that design engineers and manufacturers face during the process of bringing a device to production. It also outlines solutions and offers best practices to improve the cleaning and coating process (see the sidebar, “User Tips for Cleaning and Coating Professionals”).
 
Assessing Options
Engineers and manufacturers ultimately use cleaning and coating systems to get the best and most consistent performance out of a device. These systems also ensure that the device is sterile and ready for use once it reaches a physician.
 
When manufacturing medical devices, engineers must decide whether they must clean component parts needed for assembly, clean the final assembled product, or both. Virtually all devices will require some measure of cleaning to remove particulates, oils, or inorganic contamination that results from the manufacturing process. The challenge is to specify a cleaning process that is suitable for a variety of materials and geometries, including delicate plastic injection-molded parts, stainless-steel microtubing, or sophisticated implantable devices. Devices that may not need either cleaning or coating include silicone tubing, injection-molded silicone masks, or bulbs. For example, some silicone-molded parts may come directly from a molding machine and automatically move toward assembly and packaging, bypassing the cleaning step. 
 
When it comes to the coating process (lubrication), not all devices will require a coating. Application of a lubricant coating is generally dictated by the desired performance of the medical device once assembled. A coating is typically applied to a device that will function better with reduced friction. Any device that slides, moves side to side, or rotates may be a candidate for a lubricant coating. In addition, devices such as a syringe needle or cannula for injecting medicine or fluids may be cleaned and then coated with silicone to reduce friction when the needle pierces the skin. Likewise, mechanical assemblies that consist of multiple component parts, such as a surgical stapler, often need a lubricant coating to reduce friction and address stacked tolerances. 
 
Once the engineer or manufacturer identifies a device that must be cleaned or coated, the exact process is determined mainly by the required manufacturing volume. In low-volume production environments, basic cleaning devices such as aerosols, dry wipes, presaturated wipes with water-based cleaners, solvents, or solvent- and water-based cleaners may be acceptable. In high-volume production systems, the engineer will typically seek more automated cleaning systems to reduce costs and improve cleaning consistency. Those systems may be either solvent or water based and use machines engineered for the application.
 
Lubricant coatings applied in-house will typically be either silicone based or polytetrafluoroethylene (PTFE) based. Sophisticated surface treatment lubricants must be applied off the manufacturing premises, because they require advanced application methods to impart hydrophilic properties to surfaces that become lubricious when wetted with body fluids. 
The key factors to consider when choosing a cleaning or coating system include worker safety, equipment costs, cost per part treated, materials compatibility, required floor space, FDA approvals or ease of obtaining approvals, reduced bioburden, and ease of use. Each application will have its own unique constraints, and the best thing to do when determining the cleaning and coating system is for the design and manufacturing engineer to meet with the cleaning and coating provider to discuss specific concerns.
 
This image shows a vapor degreaser with a basket of aluminum fluid dispenser nozzle assemblies, boiling solvent, and vapor cooling coils.
Typically, the largest consideration in the cleaning process is cost-effectiveness (expressed as cost per part cleaned). Concerns prioritized after that are materials compatibility (i.e., can the fluid be used on plastic parts?), ease of use, and safety and environmental concerns. 
 
For coating and lubrication, performance is usually the number one consideration. When the device has been manufactured and is in the hands of the physician, will it perform the way in which it was designed? Following this matter (as with the cleaning process), manufacturers and engineers are most concerned with materials’ compatibility, cost, and safety and environmental issues.
 
Engineers and manufacturers will also consider the class of the device when determining the desired coating and cleaning process. Each of the three classes of medical devices determined by FDA has a different level of control necessary to ensure the safety and effectiveness of the device. Class I medical devices present minimal potential for harm to the user and are often simpler in design than Class II or III devices. They include tongue depressors, bedpans, exam gloves, and handheld surgical instruments. Class II devices are subject to more regulation because they present a bigger potential safety risk to the patient but are still typically noninvasive. These devices include x-ray machines, infusion pumps, surgical drapes, needles, and sutures. Class III devices are the most highly regulated and are life supporting or sustaining. They include heart valves, cerebral stimulators, pacemakers, and other implantable devices.
 
The type of cleaning and coating process chosen is dependent on whether the device will be invasive. For example, silicone coatings are often used on invasive devices due to their compatibility and safety in human tissues; PTFE coatings are often used on mechanical assemblies, such as surgical staplers, that function outside of the body.
 
When considering cleaning and coating options, it is important to partner with a cleaning and coatings provider that understands EPA regulations and the chemistry involved in the process. The device engineer is typically the expert in FDA regulation. However, the cleaning and coating partner should provide a dimension of expertise on EPA regulations and chemistry parameters to make the design and manufacture of the device as consistent, efficient, and sustainable as possible. Ultimately, this can save the manufacturer and designer time and money.
 

The Challenges
Cosmetics. Device engineers and manufacturers must be concerned with the cosmetic appearance of the device because they need the doctor, nurse, or patient to see a device with surfaces that are smooth and clean. The optimal surface is obtained through cleaning and coating processes that are used to eliminate cosmetic defects such as fingerprints or particulates that remain from the manufacturing process. 
 
When coating a device with a lubricant such as silicone, which can leave an oily finish, it may be necessary to remove the coating from exposed surfaces so the device is visually perfect. With other coatings, such as dry lubricants, the coating dries completely and uniformly once dipped or sprayed. 
 
Bioburden. Bioburden is a challenge in the packaging, storing, and sterilization of devices after cleaning and coating. It is quite common with manufacturers that use aqueous cleaners and often occurs when a device is not completely dry when it is packaged. 
 
Technically, bioburden is a measure of an object’s contamination with microorganisms. The presence of microorganisms on a medical device can also lead to the presence of endotoxins. Both can present challenges in delivering a sterile and pyrogen-free medical device to the end-user.
 
Many conditions can cause bioburden but fundamentally, water is a growth medium for bacteria. Therefore, removing water from the cleaning or coating process removes a growth medium for bioburden. This is why solvents are often preferable to aqueous (water-based) cleaners or coatings—because they present an environment that is hostile to bacteria growth.
 
If bioburden is not addressed, it can lead to infection when that device is used on a patient. An engineer or manufacturer who is addressing bioburden can specify a solvent-based process with submicron filtration.
 
Stacked Tolerances. One of the most familiar challenges that medical device design engineers and manufacturers face is stacked tolerances in mechanical assemblies, which can create user challenges for device actuation. This is a particularly common challenge with complex, single-use mechanical assemblies such as staplers and arthroscopic devices.
 
In engineering, the tolerance refers to the permissible limit of variation in a physical dimension. Tolerances are specified by the design engineer to allow reasonable leeway for imperfections and variability without compromising performance. Tolerances become a challenge for design engineers and manufacturers when they begin to stack up against each other. For example, when a mechanical assembly such as a medical stapler is assembled, the tolerances of each metal stamping, spring, or plastic part may begin to combine in such a way that the assembled device requires more force to actuate or execute. This issue is most common in high-volume production, when tooling used to manufacture metal stampings, springs, and plastic parts begins to wear. 
 
A partially assembled medical device consists of metal and plastic rails and a spring, which slide against each other, and is treated with a Duraglide coating. 
There are several ways that design engineers and manufacturers can deal with stacking tolerances. Engineers can choose to design everything with tighter tolerances to gain high precision. However, precision commonly leads to more frequent inspection and maintenance of tooling and fixtures during manufacturing, which drives up the unit price of a finished device. A more common way of dealing with stacked tolerances is to apply a lubricant coating such as PTFE or silicone on the finished assembly to reduce friction. 
 
Dry lubricants using PTFE particles are typically the best way for the design engineer and manufacturer to reduce the effect of tolerance stacking. In fact, many single-use medical devices that are on the market would not be commercially viable without this coating. Dry lubricants are used on many devices or mechanical assemblies found in the operating room, including catheters, cutting tools, staplers, hypotubes, and other surface-to-surface complex assemblies. 
Dry lubricants reduce the force needed to actuate or execute a device by 25–30% and provide a silky, almost effortless actuation for the medical professional performing the procedure. In comparison to silicone coatings, which are oil based, dry lubricants impart a lower coefficient of friction and are nonmigrating, so they will not transfer to packaging.
 
Maintaining Calibration. Maintaining calibration of lubricant dispersions and fluids is important to the consistency and quality of the coating and thus the performance of the device. For dry lubricants in particular, this is a top challenge for device manufacturers. 
 
The first challenge to maintaining calibration is controlling the evaporation of carrier fluid. Many PTFE dry lubricants are mixed with a carrier fluid that evaporates very quickly. This is necessary and good for the coating of the part because it dries quickly enough to leave a very consistent coating on the device. However, this also means that during the coating process, the fluid can evaporate quickly out of the vessel used for coating. In some cases, manufacturers will add an unmeasured amount of carrier fluid to maintain approximate percentage saturation, but this is not precise and can affect the quality of the coating. 
 
To control evaporation and keep fluids calibrated for maximum consistency and quality, use of process-specific equipment for the cleaning and coating process is highly recommended. This may include hermetically sealed equipment, specialized solvent recovery systems, controlled temperature baths, engineered parts feeding systems such as hoists or conveyers, or engineered application systems such as spray or brush applicators.
 
Another challenge in fluid calibration is the PTFE particles themselves. Many coatings with PTFE micropowders require constant agitation because the particles have low hang time in the liquid carrier. Low hang time means that as the fluid sits in the vessel and parts are dipped, more of the PTFE particles will sink in the fluid to the bottom of the vessel. Many manufacturers address this issue by constantly agitating the fluid. However, if done improperly, this practice can also be inconsistent and lead to streaky coatings.
 
A key solution to the short hang time of PTFE particles in a coating application is to find a provider that uses a precalibrated fluid with micropowders. For example, MicroCare Medical’s Duraglide dry film lubricants use a premixed and calibrated formula that maintains the ratio of carrier fluid to PTFE particles. In addition, a proprietary microdispersion PTFE technology deposits a thin, smooth film over the treated surface. These microdispersions suspend the PTFE in unique carrier fluids to create a more effective hang time, which results in a consistent coating and smooth device movements. 
Hang time of PTFE particles in the lubricant process can also be controlled or enhanced through the use of heat (i.e., maintaining a rolling boil of the fluid), ultrasonics, closed-loop circulation systems, and mechanical agitation. Engineers and manufacturers should also take care in choosing a method, because any of these methods to maintain agitation can also cause accelerated evaporation if not properly instituted into the process. 
 
Facilities. There are several facility challenges that manufacturers in particular face in the process of bringing the device to production. One concern is the machine footprint when selecting a cleaning and coating process. For example, how much space does the equipment need, and what effect does this have on other facility costs or incidentals? Depending on the selected cleaning system, there will be different requirements for space, electricity, maintenance, and access to water systems. 
 
In general, water-based systems have a bigger footprint than solvent-based systems. There is a wide variety and variation in the types of systems used to clean and coat devices, so it is not fair to say that one system is the most effective for reducing footprint. As a result, it is important to work closely with cleanings and coatings providers that can engineer to specific manufacturing needs.
 
Timing. Another concern for manufacturers is defining the point in the process at which they should clean and then coat the devices with lubricant. This timing affects the entire manufacturing and device delivery process. A lubricant coating is sometimes applied during the manufacturing process to assist in the assembly of the device. In other cases, it is applied at the end of the manufacturing process to ensure the ease of operation. The coating can also be applied both during and after assembly.
 
Parts should always be cleaned before applying lubrication to be certain that the coating will properly adhere to the treated surface. Lubricant does not properly adhere to a contaminated surface. The timing of cleaning and coating a device is determined on an individual basis. The cleaning or coating partner can advise the engineer and manufacturer on the appropriate timing for the specific device and system.
 

Environmental Concerns. Environmental regulations create new challenges for coating and lubrication, and this is a top concern for both manufacturers and engineers. All parties want to deliver the most effective cleaning and coating with the least environmental impact. Given the different options for cleaning and coating, there are obviously products that will have lower environmental impact than others, but this also must be weighed against all types of waste. For example, water, which is natural, can be used to clean devices, but the overall environmental impact of that system may be greater than a solvent system after considering the footprint of the system, the electricity used, the maintenance required, controlling bioburden, and the amount of water that is actually used. All factors must be weighed in determining the environmental impact—not just the product itself.
 
One factor that can reduce waste and increase sustainability is the use of engineered (versus manual) systems for cleaning and coating applications. When the process is automated, the user gains efficiencies that not only lead to consistency, but also lead to less waste. 
 
Conclusion
Overall, it is important to work with a competent cleaning and coating provider as a partner. Its experience with all solvents and equipment should help the manufacturer and engineer choose the best process for a specific application.
An important fact for engineers and manufacturers to remember when designing medical devices and assemblies is that the cleaning and coating process can play  a huge role in the performance, quality, and consistency of the finished device. Although there are plenty of challenges that can affect the process, the ultimate best practice is to find an expert cleaning and coating provider that can address any questions and concerns in a timely and educated manner. Successfully working with a partner will not only increase the quality and consistency of the process and performance of the device, but the manufacturer will also realize flexibility in the design and manufacturing process as well as achieve maximum profitability.
 
Jay Tourigny is vice president of operations at MicroCare Medical (New Britain, CT).
 

Students Recast Salad Spinner to Diagnose Anemia

The two students say the device can diagnose anemia without power and at low cost. To operate, test tubes containing 15 µL of blood are spun for about 10 minutes. The heavier heavier blood cells separate from the lighter plasma, whch is precisely what happens in an electric centrifuge. The difference is that the new device requires no electricity. The device is portable, meaning it can be brought to areas that lack such resources.

Medical Device Engineers Get New Numerical Algorithms

This figure shows the speed increases associated with using the NAG Library for SMP and multicore computer systems.

Medical device engineers seeking to improve their use of the processing power of multicore computer systems and migrate existing applications to multiprocessor architectures can download the new NAG library for symmetric multiprocessing (SMP) and multicore processors from Numerical Algorithms Group (NAG; Oxford, UK). Mathematical and statistical algorithms optimized for performance on multicore architectures have become key to progress in various aspects of instrumentation and sensor designs, advanced control engineering, innovation and manufacture of materials, and other aspects of medical device design and fabrication.

The NAG Library for SMP and Multicore contains more than 1600 routines, while this release includes more than 100 new routines. A complete list of the routines can be found here

"The NAG Library is very good for work on multiple cores because of the reliable parallel design of the algorithms," remarks Hartmut Schmider from the computational support team of the High Performance Computing Virtual Laboratory at Queen's University (Kingston, ON, Canada). "But it is also because of the common interface for both serial and multicore libraries. This enables users to speed up their code on many multiple core architectures with reduced effort."

"Most current processors are multicore and can provide benefits when programmed with parallel techniques," says David Cassell, NAG product marketing manager. "In fact, if you do not use routines tuned for multicore architectures, applications are now likely to execute more slowly. The NAG library for SMP and Multicore also has been designed to make it easy to move those applications that currently call serial routines into the parallel world by the use of common calls and common documentation. This means users can quickly gain the benefits of parallel performance."

Dosing Technology Manages Patient Safety

Keeping patient safety a top priority, a new technology helps pharmacists and technicians prepare a more accurate dose of medication. DoseEdge TPN (total parenteral nutrition), manufactured by Baxa Corp., when used in combination with calculation software and a compounder, provides automated support for TPN dose preparation, documentation, and inspection. When done by hand, TPN compounding is subject to human error. However, DoseEdge reduces the chance of error, because it can catch problems in the workflow and processes. The system also includes a bar code verification of ingredients, automated volume calculations, and photo evidence of correct measurement and injection. In addition, new security features let the user track doses via scanning outside the pharmacy. 

Predictability Competes with Confidence in 510(k) Revamp

The two aren’t mutually exclusive. But they are seen as a delicate balancing act—an act that became dangerously out of balance in recent years. From industry’s perspective, the regulators are surreptitiously changing the rules by introducing testing creep and consequent unpredictability, while from CDRH’s viewpoint, industry has been getting away with too much predicate creep—slipping complex new technologies through as substantially equivalent to 34-year-old technologies. It’s a polarization of positioning that is built around a common recognition: a revamp is overdue.

Predictability was the recurring theme from both companies and consultants who stood before CDRH officials during a recent public meeting to offer their perspectives on revamping the program.

“The current 510(k) process is beginning to hobble device development and innovation, and there is a perception that the public’s confidence in the system has been shaken,” Coombs Medical Device Consulting principal Craig Coombs told the audience. “FDA can fix both of these and thereby strengthen the process if they focus on what often works, such as establishing predictable and reasonable testing regimens for the 510(k) process today, and shift resources away from those aspects that do not contribute to public health or confidence.” Coombs said that strengthening the predictability and reasonableness of the testing process would “improve innovation, maintain public health, and regain public confidence.”

A CDRH task force is assessing the pros and cons of the 510(k) program and will soon offer recommendations on how to change it, center director Jeffrey Shuren said. The task force is operating in parallel with an Institute of Medicine review that will not prepare its report until March 2011. In the meantime, Shuren said that any changes to the 510(k) process will be open for public comment sometime in June before they are fully implemented in September.

Smith says that clearly established precedents are being abandoned, which hurts innovation and patient care.

Hogan & Hartson partner John Smith couldn’t have agreed more on the increasing unpredictability and considerable delays occurring at CDRH. He said at the meeting that longstanding processes have been altered without official announcement or explanation and that there is an increasing reluctance to accept combination or split predicates. Smith also stated that clearly established precedents are being abandoned and more nonsubstantial equivalence decisions are being rendered, among other complaints. All of this translates to increased review times and “a cumulative negative impact on innovation and patient care,” he said.

Coombs raised a few eyebrows when he advocated scrapping the current reliance on predicate devices altogether. “We need to move away from the precedent-justified system to a more truly risk-based system,” he said. Coombs acknowledged that legislation would be necessary for such a change, but he said that in the meantime, the agency needs to maintain consistent guidance on how industry develops a substantial equivalence justification.

“Since last summer, new unwritten rules for substantial equivalence justifications have emerged and caused tremendous delays in submissions and review times,” he said. These changes include an insistence on a single predicate, a rejection of the reasonable use of split predicates, and resistance to even small changes in indications for use. “Changing such a significant portion of the 510(k) process without providing prior guidance harms device development and does not strengthen the 510(k) process,” Coombs said.

CDRH should consider allowing device clearances without the need for a predicate when there is no acceptable predicate available, Medical Imaging & Technology Alliance’s Richard Eaton told the audience.

“It is becoming increasingly difficult for a device developed today to be compared with a device that is 30 years old,” he said, advocating use of CDRH’s harmonized STED (summary technical document). STED could be an approach for such clearances “because it is risk based and involves conformance to central principles to demonstrate product safety,” he said.

MED Institute regulatory scientist Daniel Dillon also said the agency should get more use out of STED in the 510(k) process. “This document requires the assessment of known and anticipated risks that may be associated with the device, and an assessment of the clinical data that are available and pertinent to a new or modified device,” he said.

The agency should consider increasing the use of special controls, according to Dillon. “We believe FDA should reopen the classification regulations for those Class II devices that present the most risk and then promulgate special controls for those devices.”

He said FDA should also increase use of the de novo classification process for new low-risk devices that have no predicate. “Any device with a new intended use and whose technology is not high risk should be reclassified via the de novo process. We believe these changes can be easily made within the existing regulatory framework.”

According to Eaton, CDRH should consider clearing devices without a predicate when there is no comparable one on the market.

Whatever changes the agency decides to make, FDA needs to address what ExploraMed general counsel Ed Bright termed as “testing creep.” He described this as a result of FDA’s lack of a firm commitment on testing requirements to obtain a 510(k) determination. Although it may seem reasonable to bump up a study requirement from 100 patients to 200 or one-year follow-up data to a two-year follow-up, such changes in requirements would cost millions of dollars that most small companies may have trouble raising in the current economic environment, Bright said.

New World Regulatory Solutions scientific affairs director Glenn Neuman complained that his group is seeing too many inconsistencies at the review level. He said a better approach would be to establish and publish clear requirements for 510(k) submissions and “hold everyone’s feet to the fire. Then we would all know what we are doing and it wouldn’t be like this black box approach that it is now. Standardizing and continually updating requirements will best protect public health and provide a level playing field.”

Neuman said device predicates should represent the accepted standard of practice, and if there is an old predicate that doesn’t meet current standards, then it shouldn’t be on the market anymore. He said FDA now is strongly recommending specific predicates for submissions. “We had a predicate rejected in an [investigational device exemption submission] in exchange for a better-known predicate by FDA,” he explained. “Just because it’s more widely used doesn’t mean it’s more accurate. Predicates are a double-edged sword and maybe the agency should use the de novo process more.” He also said the terms “intended use” and “indications for use” are confusing and they should be consolidated into one term.

Hogan & Hartson’s Smith said that in moving forward, it is important to recognize the flexibility of the 510(k) process. “You have constantly evolving products that should not be held to druglike standards.” Also, he said, the agency has to recognize Congress’ intent to gauge data requirements and match those to the device at issue.

Earlier in the meeting, CDRH had a chance to vent. Reviewers face significant challenges with “incremental design changes and device creep,” Office of Device Evaluation (ODE) engineering and science deputy Christy Foreman told the audience. She said modifications to 510(k)-cleared devices are often not submitted to the agency unless they are changes that could significantly affect safety or effectiveness or there is a modification to the intended use.

“But these submissions for modifications are based on a firm’s determination regarding the effect on safety and effectiveness,” and not FDA’s determination, Foreman said. “This information is kept in internal firm files and not subject to FDA review except during inspections. Firms often interpret the regulation, which states ‘could significantly affect’ as ‘does it significantly affect?’” Based on the latter interpretation, if the manufacturer has data showing that a change doesn’t really affect the safety and effectiveness, then the agency is not given an opportunity to reach the same conclusion.

Foreman also raised challenges about the use of predicate devices, such as when companies choose a poorer-performing device as the predicate when better-performing devices are available. They choose the poorer-performing device to make it easier to obtain a substantial equivalence determination, she explained.

Neuman says that standardizing 510(k) requirements is the best way to protect public health and provide a level playing field.

“This construct may serve to inhibit device improvements for performance for the entire device class and I don’t think that serves the public health,” Foreman said. “We also run into cases where the original device may no longer be marketed due to subpar performance, yet this device serves as a valid predicate because at the time it was equivalent.”

ODE deputy director for premarket program management Barbara Zimmerman hinted at making changes to CDRH’s third-party review program because the reviews by accredited parties are fraught with problems. She noted that about 300 (8% of all 510(k)s submitted) third-party submissions are processed annually. The poor quality of these reviews requires additional FDA resources to evaluate and address problem issues.

Zimmerman said that problems from third-party reviews are typically caused by a lack of a device-specific guidance document to help accredited parties review the application when they receive it. Also, accredited parties do not have access to previous decisions or reviews of other similar device types, unlike FDA reviewers. “We need to think through what we can do to assist our third parties in dealing with these challenges,” she said.

ODE 510(k) staff director Heather Rosecrans described challenges from having limited authority to rescind a 510(k) clearance. “In the absence of a robust rescission authority, it is difficult for FDA to address problematic predicates,” she said at the meeting. A rescission regulation was proposed in 2001 but was never finalized.

Another challenge highlighted by Rosecrans results when FDA collects postmarket safety information on a certain device type, and then the agency asks for new information to address a safety signal seen in devices currently under review. This can create an inequality perception among those arguing for a level playing field, which Rosecrans believes more regulatory authority would address. She also said the agency has concerns about final printed labeling not being required before or after devices are cleared—the center often finds that manufacturers make changes to the draft labeling without FDA clearance when such changes could require a new 510(k), she explained.

“We believe increasing transparency is essential for all of our stakeholders and for the FDA staff,” Rosecrans said in summarizing FDA’s perspective. “Achieving consistency is critical…and developing clear definitions, guidance, and additional authorities may be required, which would all go through a public process.”
 

Endoscope Manufacturers Warned About Steris System 1

Ulatowski said that devices are misbranded if devices if they are labeled for use with the SS1, pictured here. Image courtesy of STERIS CORP.

A recent letter to endoscope manufacturers from CDRH compliance director Tim Ulatowski warned them of possible misbranding of reusable devices labeled for reprocessing by the Steris System 1 (SS1) processor.

He reminded them about a December FDA notice in which the agency informed healthcare facilities that Steris Corp. had significantly modified the SS1 and that FDA had not approved or cleared this modified product. Ulatowski said that if devices are labeled for use with the SS1, then they are misbranded under section 502(f)(1) of the Federal Food, Drug, and Cosmetic Act because they fail to bear adequate directions for use.

The letter recommended the companies follow four steps:
1. Immediately review all labeling, including online information, for references to SS1 and revise it to comply with requirements.
2. Consider adding the notice: “The Steris System 1 (SS1) is not a legally marketed device,” and that the company’s labeling will be revised to identify reprocessing methods using legally marketed devices.
3. Take immediate action to validate at least one reprocessing method using legally marketed devices if the SS1 is the only method described for reprocessing your device.
4. Determine whether your labeling changes require a premarket approval (PMA) or 510(k) submission.
     a. Relabeling a product approved in a PMA may require the submission of a PMA supplement.
     b. Relabeling a reusable device cleared in a 510(k) premarket notification may require the submission of a new 510(k).


Legal Battle Forces TMJ Implants to File for Bankruptcy

In the wake of a long legal battle with FDA, TMJ Implants Inc. (TMJI) CEO Robert W. Christensen announced to close sympathizers in April that he is filing for Chapter 7 bankruptcy.

TMJI's CEO again took to his YouTube channel recently to discuss FDA's "biased, corrupt" overregulation of the medical device industry.

What pushed him to this step, he told FDA Webview, was a March 30 letter from FDA associate chief counsel for litigation Tara Boland that offered him 10 months to pay $340,000 in civil money penalties for not filing 17 disputed MDRs. Christensen had asked for 10 years to pay, in light of his and the company’s financial condition. Boland attached an agreement form that demanded $170,000 immediately and $17,000 a month thereafter plus 7.5% interest on late payments.

Christensen says bias against his devices by CDRH dental devices chief Susan Runner was first revealed in 1999 when she ordered his two prostheses off the market pending reclassification into Class III. She then expedited a competitor product by TMJ Concepts Inc. while delaying action on his. According to Christensen, Runner said that TMJI’s devices were 1960s technology that should be modernized.

“It was Runner who told me a week before the first panel hearing in May 1999 that I shouldn’t come back to the panel as we would not prevail,” Christensen said in an e-mail to the author of this column. “Give me a break! I told her I would think about it overnight and get back to her. I did and said we are coming. TMJI’s presentation was a million times better than TMJ Concept’s. Dr. Skinner, the lone orthopedic surgeon on the committee, said ‘nice presentation’ to me right after it. He knew we were correct.” That panel meeting voted to recommend approval of both of Christensen’s two prostheses, but Runner and her staff allegedly did not want his biggest seller (a unique partial metal-on-bone joint) on the market, so it was deferred by Runner to a different panel meeting a year later.

At that second meeting, which Christensen says was “rigged,” the panel voted not to recommend the partial joint’s approval. After a 19-month delay during which the company lost $6 million, CDRH approved the first, low-sales full prosthesis (TMJ Concepts’ competing device had been approved in two months and had gained a substantial market lead). The following month, over staff objections, then Office of Device Evaluation director Bernard Statland approved TMJI’s partial joint.

Christensen’s troubles weren’t over with the staff-resisted return of his bestseller to the market. As he continued to complain internally about the injustice he believed he had suffered, including demands for HHS Inspector General and FDA Office of Internal Affairs investigations, other FDAers had their feathers ruffled and resented his refusal to “just get over it,” Christensen alleged.

Twelve months later, FDA struck again. This time it conducted a two-week inspection of Christensen’s MDR files that prompted a warning letter six months later, beginning TMJI’s  mortal second battle with the agency over 17 incidents that FDA said should have been the subject of MDRs. Christensen disagreed, starting a hair-splitting war of words over whether disease-progression surrounding an implant is a reportable MDR “event” involving a “serious injury” that might be viewed as implicating his device.

Mindful what market damage his FDA competitor TMJ Concepts could wreak with those 17 MDRs, Christensen took the battle all the way to the 10th Circuit Court of Appeals, losing at every stage. Each review level was apparently convinced by the rubber-stamping below it in a “perfect” paper record.

Christensen told me that throughout the MDR civil money penalties ordeal, “I kept showing FDA and HHS I owned nothing but a poor company….I used our millions to bring the company through the approval process, never asking anyone else for help. It cost us millions, to the point I am now penniless.”

The protracted legal battle waged with FDA leaves Christensen jobless, in debt to the tune of hundreds of thousands of dollars, and lacking the wherewithal “to pay our home mortgage. It will be lost.”

A New Perspective on Medical Device Certification

The third edition of IEC 60601-1 will soon become de facto mandatory for certification of medical devices. This standard is unique, combining both product and process requirements into a single document. And by design, it specifically supports the innovation necessary for breakthrough technologies in the medical device industry. The standard accomplishes this by requiring manufacturers to utilize a product life cycle risk management process to understand and mitigate risks that are likely with any new technology or application. In short, a manufacturer must show that it has a risk management process in place and that all risks were identified and addressed such that they are acceptable according to the manufacturer’s policy on risk acceptability.

Formal assessments of a manufacturer’s risk management process will be a new activity for product certification bodies. ISO 14971 also requires a continuous life cycle approach—starting at design conception and following through to end of the life of the product. And because risk management requirements are woven throughout the fabric of IEC 60601-1 (there are approximately 115 references to “inspection of the risk management file”), certifiers and standards bodies such as the IECEE (IEC System for Conformity Testing and Certification of Electrotechnical Equipment and Components) may face a challenge in determining how best to perform assessments under these new requirements.

With product life cycle risk management becoming a new required element of certification, both the manufacturer and the certification body have a regulatory reason to explore new processes for delivering value to their customers. This situation also presents an opportunity to use advanced process design methodologies, such as lean, to create and optimize a certification method for this new, combined, product/process standard. ISO 14971 provides an internationally developed framework for risk management, which, by design, applies throughout the life cycle. This article discusses the details of the applicable requirements, and how lean process design techniques can be leveraged to create a new certification model. Such a model could be helpful in meeting various requirements, including IEC 60601.

Unique Complexity of the Device Industry

Figure 1. (Click to enlarge) Product life cycle certification model. 

The medical device industry faces numerous challenges in bringing a new product to market. Technological advances continue at an ever-increasing rate, bringing with them the opportunity for new methods to diagnose and treat patients. However, potential benefits in the diagnosis and treatment of patients must be balanced against harm that may occur. When all potential effects are not immediately understood, manufacturers of medical devices must maintain an ongoing process to identify, quantify, and mitigate risks. This process begins at the very earliest stages of product conceptualization and continues throughout the product life cycle, including the ultimate end of life for the product.

The latest generation of international consensus standards for medical device certification includes the following:

?    ISO 14971, “Medical Devices—Application of Risk Management to Medical Devices.” 
?    IEC 60601-1, “Medical Electrical Equipment—General Requirements for Basic Safety and Essential Performance.”
?    ISO 17020, “General Criteria for the Operation of Various Types of Bodies Performing Inspection.”

Many of the requirements in the standards are applicable at different times, and they represent discrete activities that must be completed from stage to stage. And although the discrete activities are completed at differing stages, they are nonetheless integrated and interdependent—forming a continuous process. ISO 14971 is clearly the main driver for this continuous safety assurance process. It states, “It cannot be emphasized too often that risk management does not stop when a medical device goes into production…With the postproduction information, the risk management process truly becomes an iterative closed-loop process.” Figure 1 illustrates the timing for the application of each of the standards noted above in the context of the product life cycle.

Note that ISO 14971 includes requirements for organization-level risk management and control. These requirements can be thought of as a sort of infrastructure that must be in place, not only before beginning a new product design, but throughout the entire life cycle of any product that may be produced. Additionally, this infrastructure supports not only individual products, but any range of products that may be produced by a manufacturer. The following elements are included:

?    Management commitment (clauses 3.1, 3.2, 3.3, and 3.4).
?    Risk management system support (clauses 3.5, 3.6, and 8).
?    Risk management process and control (clauses 4, 5, 6, and 7).
?    Process and product monitoring (clauses 3.3 and 9).

Additionally, ISO 14971 includes product risk assessment requirements for manufacturers to apply the above infrastructure in identifying, analyzing, evaluating, and mitigating the risks associated with a specific product. These activities typically first occur during the manufacturer’s research and development and design and validation stages, but per the ongoing process required by the infrastructure, they are continuously reassessed based on field experience. The specific requirements include:

?    Device-specific risk management plan (clause 3.5).
?    Risk management traceability matrix (clause 3.6).
?    Risk analysis (clause 4).
?    Risk evaluation (clause 5).
?    Risk controls (clause 6).
?    Overall risk evaluation (clause 7).
?    Risk management report (clause 8).

As the product moves through the design and validation and prototype manufacturing stages, IEC 60601-1 and ISO 14971 are jointly applied in product testing and risk mitigation. In this joint application of requirements, certain decisions that are dependent on the risk management process must be made, such as the following:

?    Applicability of specific requirements.
?    Options for risk control.
?    Modification of specific tests.
?    Selection of particular tests.
?    Changes to pass-fail criteria (subject to clause 4.5).

Once into the mass manufacturing and service and support product life cycle stage, the surveillance and ongoing risk assessment requirements from ISO 17020 and ISO 14971 apply. ISO 17020 is a standard that provides requirements for certifiers performing inspections of products, processes, and work procedures. The purpose of the inspections is to determine the ongoing conformity of products, processes, and work procedures with requirements. The results of these activities are subsequently reported to clients and, when required, to supervisory authorities (regulators). This standard notes that inspections of a product or facility may concern all stages during the lifetime of these items, including the design stage. This is an important consideration because, as previously noted, ISO 14971 is applicable to products and organizations throughout their life cycle.

Certification Process

In sum, the standards have introduced new requirements for the manufacturer’s process steps that must now be included as part of the assessment performed by conformity assessment bodies. (In this context, an assessment is the method by which conformance with a given set of requirements is established for a process or device. Without being prescriptive, the method could be a document review of objective evidence, an on-site audit, or other means.) Ideally, a new certification model would integrate product and process requirements, appropriately time the discrete activities associated with each of the OEM’s process steps, and continuously apply all steps well after the initial certification and product launch. To that end, lean process design offers some help in developing adjustments to the certification process.

Applying Lean Principles to Product Certification

As a medical device moves through the life cycle and approaches product launch, many key decisions are made by the manufacturer regarding not only basic form and functioning, but also specific materials, subassemblies, manufacturing tooling and dies, manuals, and other facets. Once these decisions are made, any revision to a product can increase costs exponentially due to a cascading effect for decisions that are dependent on earlier decisions. Needless to say, significant opportunity costs may also be incurred when and if launch dates are compromised. These factors are a key motivator for one of the teachings of lean: to ensure 100% quality throughout the process.

Other teachings of lean are applicable to the process as well—for example, the concept of continuous flow. ISO 14971 almost seems to suggest this approach as a requirement with its emphasis on developing a true “iterative closed-loop process.” Perhaps most important is the lean principle of designing the process around value-adding activities. This requires an understanding of which activities are truly value-adding from the final customer’s perspective, i.e., the patient or end-user. It is difficult to imagine what could be more value-adding than safety from the perspective of a patient or user, thus the importance of considering risk management throughout the life cycle.

An Adjusted Model

In applying these principles to medical device certification, the discrete activities previously described and depicted in Figure 1 would include, as near as possible, real-time validation of conformance with applicable requirements. Medical device complexity, as well as the new regulatory environment, would suggest ongoing vigilance as the most prudent course of action when it comes to product realization.

In practice, therefore, adjustments to the certification model would include some level of integration of the manufacturer and certifier tasks, performed as early in the product development cycle as possible. This model would potentially include the following elements.

Early Dialogue. One critical aspect is an early and planned continuing engagement between the manufacturer and the certifier. This communication is intended to reduce uncertainty regarding information needed by a certifier to begin an investigation (ensure 100% quality), inherent delays in acquiring and submitting the information (continuous flow), and multiple non-value-adding administrative start-up activities if and when design iterations are resubmitted (continuous flow).

Concurrent Certification Reviews of Design Options. As a design staff develops options and alternative product configurations, they may interpret requirements differently from certifiers, often leading to rework. By moving the certification review to be concurrent with interpretation and application of requirements by the designer, certification engineers can clarify and align interpretations, thus eliminating a costly source of rework and delays (ensure 100% quality, continuous flow, design around value-adding activities).

Simultaneous Design and Test Program Development. As the design progresses, the integration of tasks with certifier assessments allows real-time feedback about design options as well as trade-off analyses regarding test programs, development timelines, and other considerations (ensure 100% quality, continuous flow, design around value-adding activities). 

Integrated Development and Certification Testing. Development testing results may qualify for certification testing (with ISO 17025–based controls). This eliminates redundant testing and additional waiting time (continuous flow).   

Final Review Checklist. Because the bulk of value-added engineering work is performed early in the product life cycle, much of the final review prior to issuing certification is validating the compliance of testing results; that is, earlier assessment activities will have already validated compliance with constructional and risk management requirements (ensure 100% quality, continuous flow, design around value-adding activities). The difference in final review is a key enabler for meeting schedules, since the most costly and significant time delays associated with certification are issues identified at the final step in the process prior to certification. 

ISO 14971 Certification. As already noted, ISO 14971 is a continuous life cycle approach to product safety. After initial certification, the manufacturer continually seeks to identify new information that will lead to enhanced product safety, and when found, closes the loop by feeding this information back into the continuous risk management process for action. Ongoing assessments of this process validate the manufacturer’s continued conformance with these requirements and serve as evidence to regulators of compliance (ensure 100% quality, continuous flow, design around value-adding activities).  

Following this model may significantly reduce compliance issues and overall product development cycle time. Both the manufacturer and the certifier benefit from enhanced communication and placing technical expertise where it adds the most value in the overall process flow. Additionally, such a model would enable demonstrated compliance with internationally recognized consensus standards.

Conclusion

With the adoption of the third edition of IEC 60601-1, many devices will need to be recertified, some products will need to be redesigned, and entirely new products continue to be developed. As the watershed event of the first standard requiring a life cycle risk management process continues to approach, a certification model that additionally integrates and applies lean process improvement would be beneficial to manufacturers.

Mark Leimbeck is program manager, health sciences, at Underwriters Laboratories Inc. (Northbrook, IL).

Iran: A Missing Piece of the Puzzle

There is an important export market for U.S. medical devices that manufacturers may not know about: Iran. Despite the imposition of strict economic sanctions that generally block all U.S. exports to Iran, U.S. law specifically permits companies to obtain licenses from the U.S. government to export medicine and medical devices to Iran. As a result of this statutory allowance, many medical products are widely available and legally sold in Iran today.

Iran, with a population of more than 71 million, is a significant market for medical devices. Imported medical devices account for at least 95% of its market, and in 2006, Iran’s medical device imports were valued at $311.4 million. This figure is expected to rise to $422 million by 2013. Accordingly, U.S. manufacturers and exporters of these products should familiarize themselves with the regulations governing exports to Iran, both to take advantage of U.S. law and to provide needed medical products to this large and growing market. This article explains the details of the export program, describing which transactions are allowed, the requirements for lawful contracts, the financing options available, and the details of the licensing process. It also identifies common pitfalls and transactions that are not permitted by the program. 

An Exception to the Rule

Since 1995, U.S. law has prohibited the exportation of U.S. goods, services, and technology to Iran. U.S. companies also may not export items to third countries if they know (or have reason to know) that the items will subsequently be transferred to Iran, or incorporated into items transferred to Iran. However, in 2000, Congress enacted an exception to these general rules for medicine and medical devices. The Trade Sanctions Reform and Export Enhancement Act of 2000 (TSRA) required the U.S. government to terminate all unilateral trade sanctions that restrict exports of medicine and certain medical devices, which presents a valuable opportunity for U.S. device companies. 

This statutory exception also permits exports to third countries such as the United Arab Emirates (UAE) that are specifically intended for resale to Iran. Under the licensing process described in this article, U.S. companies may ship products to Iran through third countries such as the UAE, or export medical devices to international distributors, knowing that some devices will be resold to Iran.

All medical device exports to Iran are subject to a licensing requirement, i.e., exporters must receive a license before legally shipping medical devices there. This export program, as well as all economic sanctions more generally, is administered by the U.S. Treasury Department’s Office of Foreign Assets Control (OFAC). OFAC’s practice in granting these licenses has been quite favorable. In fact, in the first two quarters of 2009, OFAC received more than 400 applications to export medical devices to Iran, and only denied four applications. Bear in mind, however, that the processing time for license applications has recently been about two to four months.

Scope of Export Licenses

TSRA and OFAC’s implementing regulations cover medical devices as defined in section 201 of the Federal Food, Drug, and Cosmetic Act: 

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them; intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or intended to affect the structure or any function of the body of man or other animals; and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

A critical requirement for covered medical devices is that they must not appear on the Commerce Control List (CCL) in the Export Administration Regulations (EAR). The EAR are the principal U.S. export control rules for commercial items, administered by the U.S. Commerce Department’s Bureau of Industry and Security (BIS). The CCL is a list of specific goods, software, and technology that require licenses for export to certain countries and end-users or for certain end uses (see the sidebar, "Online Resources for Exports"). Any item not specifically listed on the CCL is considered “EAR99,” a classification given to nonsensitive items that do not generally require an export license. (Keep in mind, however, that the separate sanctions programs enforced by OFAC require licenses to export almost all items to countries such as Iran, even for EAR99 items.) Although most medical devices are classified as EAR99, some devices—including devices and parts related to vaccines and biological and chemical products—are not eligible for export under the TSRA program.

The statute that authorizes exports of U.S. medical devices to Iran also requires that all such exports be subject to one-year licenses issued by OFAC. In particular, a license issued by OFAC typically covers contracts entered into during the one-year period beginning on the date the license is issued. Then, the products may be shipped within a one-year period beginning on the date the contract is signed. So a license may, in theory, provide coverage for two years of shipments. For example, if a license were issued on January 1, 2010, it would authorize sales contracts made throughout 2010, and shipments made pursuant to a contract signed on December 31, 2010 may continue throughout 2011. Although a one-year license period is brief, it is relatively simple to renew a license once a company has prepared the initial application package. The renewal process is the same as the original application process, and companies may submit a new application every year (if needed) several months prior to the expiration of the current license.

Device firms may also enter into contracts for the export of medical devices prior to issuance of a license, as long as the contract expressly provides that performance under the contract is contingent upon receipt of an OFAC license. These so-called executory contracts are deemed to have been signed on the date of the license’s issuance, thereby permitting shipments under that contract during the next year. Also, while OFAC’s regulations do not specifically address which shipments are subject to the one-year period, it is a reasonable interpretation that this requirement applies only to the initial export from the United States. A distributor or intermediate consignee may ultimately ship the device to Iran after the one-year period.

In addition to the export of the actual medical device, OFAC’s regulations also authorize all transactions “ordinarily incident to a licensed transaction and necessary to give effect thereto.” This provision covers basic transactions that are reasonably required to complete the export transactions, including arranging transportation, insurance, and financing. It could also include the provision of basic operating manuals and other information required to install and safely operate the medical device. However, this provision does not extend to transactions or exports that are not strictly necessary to effect the particular sale and delivery. For example, it would not authorize service and repair, ongoing customer support, or the provision of training or other engineering information. To provide these or other enhanced services, a company must request specific authorization from OFAC, either in the original or a subsequent license application.

In fact, OFAC regulations (and export licenses) prohibit the export of technology or software used to design, develop, or produce medical devices. Therefore, while there is room for interpretation of what constitutes a transaction “ordinarily incident” to the licensed export, exporters may not provide production or engineering technology. In terms of technology and technical data, companies may only export basic information for installation, operation, and troubleshooting.

OFAC has recently issued guidance on when the export of replacement parts for medical devices is automatically authorized as a transaction “ordinarily incident” to the original licensed export. Replacement parts are covered under the original one-year license as long as they are separately classified as EAR99 and are shipped within the validity period of the original license. As described later, exporters may need to obtain a classification ruling from BIS to confirm an item’s EAR99 classification. To ship replacement parts, those parts must have separate classifications. Exporters may not rely on an EAR99 classification issued for the medical device as a whole. If replacement parts are needed after the original license has expired (i.e., the license under which the actual device was shipped), the exporter must submit an additional license application to export the replacement parts. Moreover, if a device exported under this program must be reimported into the United States for repair, the exporter must apply for a separate license. Both of these license applications should include a copy of the original application and license. Also, an import application should describe the circumstances under which the device came to need repair, and explain what repairs will be done.

Applying for a License

Exporters must first obtain a license before shipping any products destined for Iran. OFAC’s regulations outline set forth specific application procedures for export licenses under this program. Manufacturers should review their applications carefully because incomplete applications are returned without action. An application package must include the following elements:

?    The applicant’s legal name, state of incorporation, and contact information.
?    Names and contact information for all parties with an interest in the transaction, including financial institutions, distributors, brokers, purchasing agents, and end-users. If the device is exported to a purchasing agent in Iran, the applicant must identify the agent’s principals at the wholesale level for whom the purchase is being made. If the device is sold to an individual, the applicant must identify any organizations with which that individual is affiliated that have an interest in the transaction. 
?    A description of all products to be exported under the license, their intended end use, and an explanation of how the products meet the definition of a medical device.
?    Documentation showing that the products are all classified as EAR99. Numerous devices have already been classified as such (see the sidebar). For devices not on this list, the applicant must first receive an official EAR99 classification ruling from BIS. This is a separate application made with a different agency, and it should be prepared by export compliance personnel or a lawyer. A commodity classification request may require a month to process, so firms should consider the need for an EAR99 classification ruling at the beginning of the export license process. 

Note that companies may only apply for an export license (and a classification ruling) for individual products, not an entire product catalog. However, companies may group together categories of products that are generically similar and consider them one product. For example, if 100 stainless-steel orthopedic screws in a particular product line all have the same composition and function and only vary in slight dimensions, these parts may be considered one product. Companies should also request an EAR99 classification ruling for all parts and subassemblies that may need to be exported separately from the complete device.

Finally, applicants must ensure that no party identified in the application is a restricted party and that the exported products are not intended for any restricted end use. OFAC maintains a list of persons and entities with whom U.S. persons may not transact any business called the Specially Designated Nationals (SDN) List. Prior to submitting a license application, applicants must determine whether any party involved in any stage of the transaction appears on the SDN list—
including financial institutions. There are many Iranian SDNs, including many of the major Iranian banks. If an SDN is possibly involved, the transaction must be restructured so that no SDN is involved. Also, a company may not export a medical device if it knows (or has reason to know) that the device will be used for a restricted end use, such as the development of chemical or biological weapons.

Financing of Exports

U.S. law is also very specific about the types of funding permitted for export to Iran. The following three payment arrangements are generally authorized: 

?    Payment of cash in advance.
?    Sales on open account, provided that the account receivable may not be transferred by the person extending the credit.
?    Financing by financial institutions in third countries. 

Although some European banks are reluctant to finance transactions with Iran (often under U.S. pressure), banks in the UAE and third countries routinely finance trade with Iran through letters of credit. Also, U.S. banks may confirm or advise financing by third-country financial institutions. In addition to these three options, OFAC may authorize alternative payment arrangements on a case-by-case basis if a license application includes such a request. However, it is unlikely that OFAC would authorize direct financing by a U.S. or Iranian bank. Finally, a commercial export to Iran under this program may not be made with U.S. government assistance.

Conclusion

Companies should be careful not to overlook applicable export exceptions and consequently forego valuable business opportunities. Exporting medical devices to Iran is one of these opportunities. U.S. companies can legally export medical devices to Iran and take advantage of a significant market if they are aware of this program and comply with the requirements.


Michael Gershberg is an associate at Steptoe & Johnson LLP (Washington, DC).