Medical Device Link.

Originally Published January 2001

Establishing Substantial Equivalence of Reprocessed Single-Use Devices

In light of the recent FDA enforcement decisions, companies submitting reprocessed SUDs for premarket review must pay careful consideration to scientific and regulatory considerations.

David L. West, Timmie Topoleskie, and William MacFarland

FDA has announced an intention to extend its enforcement of the premarket notification requirements of the Federal Food, Drug, & Cosmetic Act (FD&C Act) to reprocessors of single-use medical devices (SUDs). This is a major reversal of a policy established just two years ago.

Under the new policy, published in Guidance for Industry and for FDA Staff: Enforcement Priorities for Single-Use Devices Reprocessed by Third Parties and Hospitals (August 2, 2000), a reprocessor will be required to submit data to FDA for each type of device it reprocesses. These data must be of sufficient quality and quantity for FDA to find that the device is safe and effective in reuse, or that it is substantially equivalent to another legally marketed device, such as the original disposable device. Any reprocessed device unable to meet this standard presumably will be denied approval or clearance for sale and thus will be removed from the market.

While FDA has said it will require premarket submissions for reprocessed devices, it has not elaborated on the substance of what must be included in them. The agency has not yet provided formal guidance to the reprocessing industry, or to its own reviewers, regarding specific data that will be required to clear or approve a reprocessed device. Reprocessing a device that was designed for only one use introduces many new technological characteristics into the device and raises significant questions not considered in previous device reviews. This article addresses some of those issues and proposes questions that should be asked in reviews of premarket submissions for all reprocessed SUDs. Through a discussion of design considerations and of data on reprocessed devices, it explores the effects of reprocessing on key areas of product integrity, sterilization, biocompatibility, shelf life and packaging, and labeling, and suggests the kinds of submission data needed to address those effects.

The purpose of this article is to suggest regulatory and scientific requirements for the marketing of used and subsequently reprocessed SUDs to ensure that each device is as safe and as effective as its new counterpart. It is to be hoped that this discussion will open a dialogue in the scientific and regulatory community that will result in effective FDA reviews of premarket submissions for these products—reviews that could prevent unsafe or ineffective devices from being used on patients.

EMERGENCE OF THE REPROCESSING ISSUE

Medical devices are articles defined by section 201(h) of the FD&C Act and are regulated under the authority of FDA (see insert below). Historically, disposable, so-called single-use medical devices have been understood to be devices conceived, designed, and manufactured for use in delivering care to one patient and then disposed of afterward.

Recent economic and social factors, however, exerting pressure to contain or reduce healthcare costs, have led to the common practice of reprocessing disposable medical devices for reuse on one or more additional patients. In some circumstances the reprocessing is performed by the user facility. But reprocessing of disposable devices has become so widespread that an industry of commercial reprocessors has emerged to collect used devices from user facilities and reprocess and resell them on a large scale. As a result, disposable medical devices are often reprocessed several times and used on multiple patients.

Despite its authority to regulate SUD reprocessing strictly, FDA has for years exercised regulatory discretion in ignoring reprocessors' failure to comply with certain elements of the FD&C Act. Reprocessed SUDs have not been subject to FDA clearance or approval for use in patients.

FDA premarket review is intended to investigate and uncover patient-safety issues through an examination of the device and its intended use. Only after successfully completing the premarket review process are complex medical devices permitted to be sold in interstate commerce.

In justifying its past decision to ignore reprocessor noncompliance with the premarket requirements, FDA in 1998 issued a call for data demonstrating safety risks posed by reprocessed disposables.¹ Those data are now beginning to be revealed and their implications understood.

In light of growing concerns raised by the emerging data regarding the safety of reprocessing, FDA made its decision to increase regulation of reprocessed disposable medical devices through enforcement of all aspects of the FD&C Act, including submission of marketing applications to the agency for review. This involves requiring premarket notifications (510(k)s) or premarket approval (PMA) applications for some, but not all, reprocessed devices.

Because most medical devices are cleared through the 510(k) process, and because the vast majority of devices that are both disposable and economic candidates for reprocessing are not subject to PMA requirements, the body of this article will refer only to the 510(k) regulatory path. The discussion encompasses devices that traditionally have been regulated under the premarket notification process and also those that are, by regulation, exempt from premarket notification. However, the safety and effectiveness issues considered below in the context of devices regulated under section 510(k) of the FD&C Act would also apply to devices subject to PMA requirements.

PREMARKET NOTIFICATION AND REPROCESSED SUDS

In determining substantial equivalence (see insert), FDA examines whether the device in question is at least as safe and effective as the device to which it is being compared (the "predicate device"). FDA has established and disseminated many policies to ensure that these determinations of substantial equivalence serve the agency's public health mission, are scientifically sound, and collectively provide a predictable, orderly, and equitable regulatory process.

The most notable policy was issued in 1986 and established the 510(k) decision tree and rationale.² The 510(k) decision tree involves determining substantial equivalence through a series of questions that probe, with increasing focus, the device's intended use and its technological characteristics (Figure 1). Requiring data from submitters of 510(k)s is the only way that FDA can determine, in a rigorous and systematic manner, whether the subject device is comparable to the predicate device. For legal and practical considerations to be satisfied, the subject device must be at least as safe and effective as the predicate device to be found substantially equivalent.

A 510(k) submission typically includes, in addition to various summaries and administrative information, the following elements:

• Device classification information.
• Labels and labeling, covering product identity, intended use, indications for use, and directions for use.
• A description of the device, its technology, and its mode of operation.
• Device design and performance specifications.
• A comparison of the device's indications for use and technological characteristics to those of a predicate device.
• Performance data, sometimes including clinical data.
• Manufacturing information.
• A 510(k) summary or statement.

To date, reprocessed devices have not been involved in the classification or 510(k) processes. Current device classifications (see insert) are based on the collective clinical experience of OEM devices. They were not intended to cover reprocessing or reprocessed devices. Because the reprocessing of disposable medical devices is a relatively recent phenomenon, and because the practice has not been satisfactorily described, reprocessed devices cannot be assumed to have contributed significantly to the collective clinical experience supporting FDA's classification of a specific device.

Moreover, the collective clinical experience supporting classifications of OEM devices cannot be assumed to attest to the safety or effectiveness of reprocessed devices. Reprocessed devices should not be deemed equivalent to their OEM counterparts without rigorous challenge in the context of a 510(k) review process designed to examine the technological characteristics that distinguish reprocessed devices from OEM devices.

New Technological Characteristics. A reprocessed product differs from the OEM version in having technological characteristics unique to reprocessing. These new technological characteristics arise because the device was designed by the OEM to be used only one time and is now being considered for use more than once.

In accordance with FDA's 510(k) guidance, the new characteristics must be taken into account in a 510(k) review. It is the agency's policy that a medical device may have new characteristics relative to the predicate device, but that accepted scientific methods must exist for assessing the effects of those characteristics on the device's performance, and that performance data must be available.

For FDA to apply its policies consistently and to ensure scientific integrity in the review of 510(k)s, it must make certain that the new technological characteristics are described in reprocessed-product 510(k)s, and that performance data assessing relevant safety and effectiveness issues are included. As with any 510(k), the submitter (here, the reprocessor) bears the burden of identifying validated methods for assessing the new technological characteristics and the safety and effectiveness issues associated with them.

To appreciate how reprocessing introduces new technological characteristics, consider the unavoidable differences between any new device and its reprocessed counterpart. The incoming "starting material" used by the reprocessor to manufacture the reprocessed device (that is, the used device) is of unknown quality, in contrast with the starting materials specified by the OEM.

Original-device manufacturers typically perform quality tests on starting materials. For example, a manufacturer of surgical staplers, upon receiving a lot of polycarbonate to be used in manufacturing the device handles, will randomly sample the polymer pellets for quality testing. Such testing, in order to be meaningful, is necessarily destructive. If the samples pass the quality test, polymer pellets from that lot are then used to manufacture the stapler handles. The OEM can use random samples to characterize an entire lot of material because that material is made using validated processes that result in a homogeneous product.

Reprocessors, however, do not obtain a homogeneous lot of raw material and thus cannot perform traditional material testing. Testing performed by the reprocessor is limited to that which will not alter or destroy the device. Such testing is naturally incomplete because it cannot uncover latent defects that could lead to device failure. Even testing every single device in this way will not provide the assurance of material integrity possible with random destructive material testing.

Moreover, the reprocessor's incoming material has a use history that may not be known with certainty and will be different for each device. Yet the history of each device is central to its quality as a reprocessed product.

The new technological characteristics of the reprocessed device raise important questions in the following areas, each of which must be addressed by proper performance data.

• Product physical integrity.
• Sterilization and cleaning.
• Biocompatibility.
• Shelf life and package integrity.
• Labeling.

The answers are critical to a finding that the reprocessed device is substantially equivalent to—that is, as safe and effective as—the predicate device. For original devices, these questions are typically addressed by either design verification or validation as required by FDA's quality system regulation.

In view of the substantial changes in an SUD brought about by reprocessing, and of the existing evidence of reprocessed-device failures, reprocessed devices cannot be presumed equivalent to their OEM counterparts. The reprocessor must address this issue prior to patient exposure, in a premarket submission. The existence of substantial data showing serious product defects exhibited by reused devices found on hospital shelves suggests the inadequacy of the FDA inspection authority to control these safety issues effectively.

Performance Data. In reviewing performance data, FDA reviewers should keep in mind that the new technological characteristics involve both product design issues and process issues. This means that performance data for reprocessed-device 510(k)s will normally include both design verification testing and process design verification testing.

Design verification and process design verification questions that should be asked in reviewing reprocessed-SUD performance data to address new technological characteristics introduce each of the following discussions on the areas of concern identified above. Each discussion considers some of the performance problems that have been reported, as well as other problems that could arise.

PRODUCT PHYSICAL INTEGRITY

New technological characteristics introduced by reprocessing raise questions about product physical integrity such as the following:

• Have performance specifications been established that translate into adequate clinical performance? How will the device be tested for conformity to those specifications?
• How are nonobvious OEM design changes detected and accounted for?
• What is the extent of material and mechanical degradation following use, cleaning, and sterilization?
• How has reliability for each subsequent reuse been addressed?
• What are the potential failure modes of the reprocessed device?
• How is the test procedure designed to measure failure?
• How will the number of reuses of a product be tracked?

Regarding the last question, FDA has made clear its intent to approve reprocessed SUDs for just one additional use despite multiple-use practices already firmly established by reprocessors. Failing to require data to support the maximum allowable number of reuses is inconsistent with FDA's regulation of other multiple-use devices.

Device Use History. Whereas an OEM product has no use history, a reprocessed product may have been used once or many times, and the nonhomogeneity of that use history must be taken into consideration. The unique use history of a reprocessed device could have a significant impact on future performance. In fact, reuse of individual units of the same model of a device, all reprocessed in the same way, could lead to completely different outcomes determined by conditions of prior use, such as the anatomy of the patient on whom the device was first used.

For instance, a surgical needle previously used in scar tissue may exhibit a markedly different failure profile than a needle that has merely passed through normal tissue. Future performance and possibility of failure of these two seemingly identical needles is likely to be different. A 510(k) for such a reprocessed device would need to include performance data that assess the effects of this new technological characteristic (varying failure profile) and demonstrate equivalence to the OEM device.

Similarly, the atherosclerotic plaque that blocks the coronary arteries of angioplasty patients may differ in hardness and pliability from patient to patient. The same type of percutaneous transluminal coronary angioplasty (PTCA) catheter may thus be subjected to very different inflation pressures, material interactions, and other conditions in different patients. Such differences will affect the future distensibility of the balloon components of PTCA catheters employed to reestablish normal flow in the artery. Such balloons are designed to inflate to preset diameters. This performance feature degrades as the balloon is repeatedly stressed with reuse, and may be compromised to an unknown degree by aspects of the anatomy of patients on which it was previously used.

OEM product performance testing is concerned with initial failure. By contrast, performance testing for reprocessed products must take device exhaustion, or wear-out, into consideration. This means that, in addition to assuring that the reprocessed product meets functional specifications, the reprocessed-device 510(k) must characterize time to failure or number of uses to failure.

Because its use history is unknown and destructive device testing is not feasible, it may be impossible to inspect or test a product to determine whether it is at or near the wear-out stage of use. The 510(k) for such devices must identify alternative methods for detecting and, more importantly, predicting such wear-out. Otherwise, such failures will only be detected in use, possibly resulting in patient injury or medical error.

Material Effects of Reprocessing. In addition to prior use, reprocessing itself may alter key material and mechanical properties of the device. For example, cleaning and sterilization may introduce new failure modes to the device or accelerate the wear rate of a reprocessed product.

Some stainless steels, including mar-tensitic alloys of the 400 series, designed for maximum hardness, are used in the manufacture of disposable scalpel blades and knives. The material mechanisms that impart high hardness to these stainless steels render them especially susceptible to corrosion. Small scratches left from grinding, sharpening, or scrubbing may be readily attacked by certain cleaning and sterilization chemicals, including peracetic acid, which can lead to corrosion. Such corrosion can in turn lead to catastrophic failure of the instrument on subsequent use.

For reprocessed stainless-steel devices, then, it is imperative that the 510(k) characterize these new technological characteristics. In addition to identifying the type of stainless steel used to manufacture the device, the reprocessor would need to characterize the likely failure points on the device and the average number of cleaning and sterilization cycles the device could undergo prior to such failure.

Many studies focusing on reprocessed SUDs have reported malfunctioning or out-of-specification devices. These studies are useful in identifying changes introduced by reprocessing that must be accounted for in the 510(k).

In an FDA study of the effects of cleaning and reuse on device materials, both used and new, purposely contaminated PTCA balloon catheters were cleaned, packaged, and EtO sterilized before being analyzed. Results demonstrated that the guidewire tubes of a number of reprocessed balloons were curled up inside the balloon as a result of overinflation, while other balloons shrank due to reprocessing and EtO sterilization. Analysis of the unused balloons subjected to cleaning revealed changes in balloon diameter as much as 10% outside of the manufacturer's specification. Results also showed that reprocessed balloons were stickier than new balloons.³

One study demonstrated functional failures specific to balloon catheters. These included poor trackability, probably due to the unfolded condition of the balloon as it was removed from the package; inability of balloons to be prepared in accordance with instructions for use; curved inner bodies and S-shaped inner bodies in the balloon upon inflation for testing; and failure to withstand an average burst pressure of 21 atm.⁴

In that same study, functional failures involving diagnostic and guiding catheters included failure of reprocessed diagnostic catheters to perform as well as new catheters in two types of torque testing and signs of material degradation in the guiding catheters following tensile overload tests. All of the guiding catheters and two-thirds of the diagnostic catheters displayed out-of-tolerance shape conformance. One-third of the diagnostic catheters had outside-diameter measurements above their preestablished specifications and top inner diameters that were below preestablished specifications. Failure to withstand five injections to the pressure rating indicated on their hubs characterized one-fifth of the diagnostic catheters.

A corporate study subjected 27 reprocessed cardiac catheters to functional testing. All balloon catheters failed to perform adequately in trackability and balloon preparation tests. In addition, 9% of diagnostic and guiding catheters failed tests for shape conformance, and up to 56% of all catheters did not pass some aspect of the visual inspection, exhibiting such faults as flaking of the exit marker, kinks, bends, a sliced outer body and strain relief, or an open fuse.⁵

Clearly, resterilization and the use history of reprocessed catheters contribute many new technological characteristics to these devices, which must be defined and evaluated in 510(k)s as part of the bid for a conclusion of substantial equivalence. While much of the available data on reprocessed SUDs concerns cardiac catheters, several other device types have also been studied, including orthopedic devices.

In one study, investigators collected reprocessed devices from area hospitals to assess whether they still conformed to the specifications of a new device.⁶ Devices studied included cutting accessories, which are precision instruments designed to rotate at up to 100,000 rpm while delivering clean cuts. Results of the investigation demonstrated that attempts to resharpen a used device removed essential material, which depleted and destabilized the device, making it unreliable. The resharpening of such devices has produced misdimensioned cutting accessories and flawed instruments that could result in longer surgeries and poor surgical outcomes. Of the 213 devices analyzed, 81 (38%) had flaws in their integrity. Of these 81 devices, 23 had worn, damaged flutes.

In this case, a lack of design understanding on the part of the reprocessor seems to have led to inappropriate reprocessing. A 510(k) for such a reprocessed device would need to include data that characterize the resharpened surface and evaluate the device's ability to operate as intended. Such data would be necessary to support the claim of substantial equivalence.

A similar report revealed that an ultrasonic device blade had not been uniformly sharpened on reprocessing. Ultrasonic cutters must vibrate at a particular frequency in order to achieve their dual cutting and coagulation effect. Imperfect shaping, scratching, or other surface damage to the blade of such a device will cause it to vibrate improperly. As a result, the device may not activate in midprocedure; or it may cut but not coagulate, resulting in internal bleeding; or the blade may fracture during use, possibly depositing fragments in the patient. So that such negative outcomes may be avoided, the reprocessed-device 510(k) must demonstrate the reprocessor's clear understanding of the device's key design features and functionality.

This example demonstrates the importance of having FDA reviewers who are fully conversant with the safety trade-offs inherent in reprocessed devices. How FDA will actually decide which trade-offs are acceptable, in light of its requirement that all 510(k) devices must be at least as safe as their predicate devices, has not been addressed in the reuse guidance document.

In addition to design considerations, a reprocessed-device 510(k) must identify all the materials used in the device and account for the effects of reprocessing on each one. Reprocessing can significantly affect the integrity of a device. Postprocess testing must ensure that processing steps, including sterilization, do not adversely affect a device's material or mechanical properties. Final testing conducted before sterilization is insufficient to provide such assurance.

Damage to metals, polymers, and adhesives found in devices taken from hospital shelves demonstrates the ineffectiveness of reprocessed-device testing prior to sterilization as a control for these types of safety issues. This is not surprising from a regulatory perspective. It confirms the longstanding FDA policy that product quality and reliability cannot be achieved through device testing. These attributes must be designed into medical devices, and devices must be manufactured with validated processes to ensure reproducibility.

For instance, aluminum used to manufacture disposable intubation stylets may develop subcritical damage that leads to an undetectable flaw and then device failure. A serious injury to a surgical patient was reportedly brought about by the use of a reprocessed aluminum intubation stylet.⁷ During a difficult intubation, a 10-cm section of the disposable stylet broke off in the patient's esophagus. It was not detected until several weeks later when the patient reported acute stomach pains, which were traced to the stylet fragment having perforated the duodenum.

This incident underscores the need to have the performance characteristics of a device designed in. It also reinforces the importance of understanding how many times a device can be reused before it will fail, and of the need to provide an adequate safety margin for patients.

Testing a device before release merely demonstrates that it functioned when tested. It does not provide assurance that the device will work the next time it is used on a patient.

In the case of devices manufactured from polymeric materials, the 510(k) for a reprocessed SUD must identify the various polymers used in the construction just as the 510(k) for the OEM device must. Further, to address the new technological characteristics of these reused devices, the reprocessor needs to characterize the susceptibility of each polymer to various reprocessing changes along with the effect of such changes on both material integrity and device mechanics. Absorption of cleaning fluids, for instance, can have a plasticizing effect on some polymers and alter their mechanical properties.

In one in-house study, a reprocessed single-use trocar developed both a complex crack in the housing near the stopcock and a chip in the leading beveled edge of the trocar sleeve after reprocessing. The disinfecting solutions used in reprocessing weakened the plastic and caused it to crack at stress points.⁸ Cracks at stress points can cause a trocar to break during reuse, resulting in plastic shards in the patient.

Many single-use devices incorporate long, narrow, polymer tube components. Such components can easily bend and kink and thereby produce crazing, an alignment of polymer molecules that changes the fundamental mechanical properties of the polymer and increases the likelihood of device failure. Crazing causes the distinct white line that often forms at the point where plastic products are bent. This line signals a change in the polymeric properties and marks the most likely site of failure.

Model-by-model process design verification is essential in 510(k) review of reprocessed devices in order to ensure that devices at or near the point of critical failure are identified. In fact, FDA's Office of Science and Technology (OST) has stated, in response to results of testing in agency laboratories, that only model-by-model evaluations of reprocessed SUDs would be acceptable.⁹ The way that different polymeric materials used to manufacture similar devices may demonstrate markedly different degradation profiles over time is charted in Figure 2. Mechanical degradation can be related to fatigue, wear, loss of tensile strength, crazing, or another precursor of failure.

Figure 2. Possible polymer failure profiles, showing why it is essential to identify materials of construction in reprocessed-device 510(k)s.

The effect of multiple uses is not addressed in the 510(k) for a new single-use device. Therefore, the reprocessed-device 510(k) must identify the types of polymers used in its manufacture, along with their degradation profiles, in order to appropriately identify predictors of failure. Devices made from polymers A or C in the figure may fail catastrophically with little warning, the polymer-A device perhaps after first use. The polymer-C device may be reprocessible, but it will likely fail without warning. Devices made of polymer B may act more predictably. For devices in which signs of wear or degradation are not evident, accurate tracking of use history is essential in order to minimize the possibility of patient injury.

Most single-use medical devices are made up of several different polymers or metals. The abutment of different materials generates additional reprocessing questions. Adhesives used to join materials can dissolve or harden when exposed to cleaning and sterilization chemicals. This was the case with some models of electrophysiology (EP) catheters tested by OST: the adhesive holding metal electrodes onto the polymer catheter failed.

In other types of EP catheters, the electrode is press-fit, or crimped, over the polymer. The polymer in this case can expand and contract under reprocessing conditions, eliminating the good fit with the metal electrode. Just as the 510(k) for the new SUD would supply tensile-strength data on catheter joints, the reprocessed-catheter 510(k) must provide tensile-strength data for the reprocessed joints.

Design Changes. Finally, reprocessed-device 510(k)s must describe and justify a method for detecting design changes made by the OEM, especially nonobvious changes. Such changes may render any previous validation of cleaning and sterilization meaningless. For instance, the original maker of a disposable cuffed tracheostomy tube may change its design or the polymer used in its construction, resulting in thinner cuff materials. A reprocessor's cleaning and sterilization methods might no longer be acceptable for the device, yet, without a method for identifying such design changes, the reprocessor would continue reprocessing it as usual.

STERILIZATION AND CLEANING

Reprocessing SUDs introduces new technological characteristics relating to the sterilization and cleaning of the devices. Questions to be asked regarding these aspects of reprocessing include the following:

• To what extent does the cleaning process remove biological debris and endotoxins, or deposit chemical residue on the device?
• What is the effect of residual biological debris on sterilization? How clean must the incoming material be to ensure attainment of the sterility assurance level (SAL) specified?
• How will the cleaning process ensure the achievement of an acceptable residual level given the nonhomogeneity of incoming material?
• Can the device be sterilized to the established 10^–6 SAL consistently?
• If the user is expected to perform initial treatment steps or to comply with specific storage instructions, how and when are such instructions provided?
• What is the effect of failure to comply with such instructions? How can compliance with such instructions be ensured?

The conventional approach to sterilization and sterilization validation is to presume that the product being sterilized is well-defined and homogeneous in makeup. Reprocessors, however, do not enjoy the benefits of well-defined incoming material for several reasons.

Prior use of a device can result in the caking of biological material on its surfaces. Bioburden will fluctuate from device to device and will depend on the pathology of the patient on whom each device was previously used and the duration of that use.

Prior use and subsequent reprocessing can introduce cracking or crazing that could harbor pathogens. Highly irregular surfaces and other features characteristic of SUDs, such as low-clearance joints and narrow lumens, can shelter organisms from sterilant, making conventional methods of sterilization and validation unsuitable. In addition, prior sterilization exposures (of unknown number) can result in material changes that may lead to nonhomogeneity.

In a conventional manufacturing operation, incoming materials typically are specified to be free of particulate material, including lint and hair. The cleaning of these incoming materials is intended to remove any oils from human exposure and any contaminants left over from raw-material processing. Reprocessed products, on the other hand, present a different contamination profile and require the application of different cleaning methods and validation.

Unlike new devices, reprocessed devices have been exposed to various pathogens that would be potentially dangerous to new patients on whom the refurbished SUDs would be used. Furthermore, once blood or tissue dries on the device, significant effort can be required to remove it. Success in cleaning a reprocessed device will depend on the reaction of the product material and the soiling agents to alkaline detergents, neutralizing acid rinses, ultrasonic cleaners, high-pressure sprays, and heat from the drying process. Polymer alteration, as discussed above, can result in microscopic cracks that may harbor harmful bacteria.

Whereas conventional cleaning processes presume that incoming material has a specified level of purity, cleaning of SUDs intended for reuse needs to be designed to accommodate the uncertain nature of the reprocessed device, the potential impact of the cleaning process on device materials, and the imperative to remove any residuals that may produce toxicity.

In addition, reprocessor cleaning of long, narrow-lumened devices often involves flushing the lumens with a syringe. Such flushing may spread the contaminating material along the entire length of the lumen and may not result in adequate cleaning.¹⁰ A 510(k) submitted on behalf of a reprocessed narrow-lumened device would have to include data showing that the cleaning process is validated. Otherwise, it would not be possible to conclude that the reprocessed device is equivalent to the OEM product.

The difficulty of cleaning used disposable medical devices effectively has been demonstrated by FDA, by OEMs, and by independent researchers. First, OST studied PTCA balloon catheters that either were collected after a single use or were new devices deliberately contaminated with organisms and protein.³ Catheters in the former group were cleaned with 10% bleach and detergent with enzyme. The latter set of test catheters was sterilized with EtO only.

Devices in the first group had been contaminated by blood in the guidewire lumens. Multiple washings proved unable to remove the contrast dye in some balloon channels, resulting in crystal formation that plugged the balloon or balloon channels. In the second group, nearly half of the catheters grew organisms near the center of the lumen despite undergoing EtO sterilization.

OEM data confirm FDA's findings. In five studies of reprocessed single-use biopsy forceps retrieved from hospital stocks, one OEM consistently found that nearly 50% of all forceps were not sterile.¹⁰ Similarly, an independent hospital, in assessing the viability of performing in-house reprocessing, discovered that 56% of devices in the first batch returned to the facility by the commercial reprocessor were nonsterile.¹¹

Other researchers conducted a study on the effects of reprocessing and reusing EP catheters.¹² They tested 34 reprocessed catheters (32 treated in-house and 2 commercially) along with 39 new stock catheters that either were used as control articles or were assessed after simulated reprocessing and reuse. Significant findings included reddish-brown contaminant on the tip electrodes and excessive levels of sterilization residue and by-product residue after 10 wash/sterilization cycles.

A premarket notification must provide assurance that the sterilization methods and sterilization validation applied to reprocessed SUDs are appropriate to cope with the special issues presented by the technologies of reprocessing. Proper sterilization testing methodology is critical.

To mention one instance, results of sterility testing performed by both FDA and an OEM for the same lot of reprocessed biopsy forceps were apparently inconsistent. Further investigation led to the determination that FDA's testing method, which involved immersing the 240-cm- long, narrow-lumened devices in test broth, was likely to be inadequate for detecting possible sterilization failure in the central portion of the device because of the inability of the broth to reach bacteria located far from the end of the lumen. The manufacturer's method involved segmenting the device into 10- to 20-cm segments prior to immersion. This approach enabled the test broth to contact all internal surfaces of the lumen and provided a more accurate test of sterilization efficacy.

BIOCOMPATIBILITY

New technological characteristics introduced by reprocessing SUDs also raise the question of whether the biocompatibility of the device has been affected and, if so, whether the level of biocompatibility offered by the altered product is acceptable. The biocompatibility profile of the OEM product may or may not remain applicable to the reprocessed product, depending on the effects of prior use, cleaning, and sterilization on the device's materials and bioburden. If material and bioburden equivalence to the OEM product cannot be assured, then the reprocessed-device 510(k) must provide assurance that the impact of the product on the patient and the impact of the patient on the product are both minimal.

In studying reprocessed PTCA balloon catheters, OST noted increased stickiness in some types of reprocessed balloons.³ Reprocessing likely changes the actual surface properties of the balloon polymer in these cases. The material itself becomes rougher, signaling a change in basic material properties and in device biocompatibility. The biocompatibility profile of the OEM device may no longer be applicable or provide information relevant to the safety of the reprocessed device. Unless a claim that the biocompatibility profile of the OEM device has not changed with reprocessing can be justified, the biocompatibility of the reprocessed device will have to be assessed anew and the data submitted in a 510(k).

EP catheters provide another set of biocompatibility issues raised by reprocessing. Like all devices introduced into a major blood vessel or the heart, reprocessed EP catheters have the potential to cause formation of life-threatening emboli in the vasculature. This potential is increased when the electrode-catheter junction fails to be smooth and continuous, as was found to be the case with reprocessed EP catheters.³

Also introduced into the heart, ablation catheters are used to remove areas of heart muscle that cause abnormal electrical activity. Reprocessing-induced alterations in the steering capability and accuracy of these devices, as well as electrode defects, could lead to accidental ablation of normal tissue. This type of medical error could result in pacemaker dependence for the patient. Just as tractability and steerability are addressed in an OEM cath-eter 510(k), the reprocessed-catheter 510(k) would need to include data that characterize and evaluate performance of the device with respect to these characteristics.

Biocompatibility concerns also encompass possible stresses on the body of the patient brought about by degraded device mechanics due to reprocessing. For example, excessive distention of a polymer intubation cuff due to reprocessing-induced changes in polymer compliance can interrupt circulation to contacted tissue and thus cause necrosis. Similarly, owing to changes in cutting properties, a reprocessed saw blade may require the application of greater-than-usual pressure to cut through bone tissue. Such additional pressure, along with increased friction attributable to the dullness of the blade, results in the generation of additional heat and can therefore lead to microscopic tissue damage or necrosis in the bone.

SHELF LIFE AND PACKAGE INTEGRITY

Shelf life and package integrity questions are raised when SUDs are reprocessed and repackaged for reuse.

• How have the shelf life of the OEM device and its previous use history been accounted for in determining the shelf life of the reprocessed device?
• How has the reprocessed-device package seal been verified?
• How has the package been tested against potential breaches?
• Does the packaging adequately protect the device?

Device shelf life is a function of both sterility and material degradation. While it may be appropriate, from the standpoint of sterility, to ignore previous use history in extending the shelf life of a reprocessed device, such an approach is not acceptable from a materials perspective. To address this new characteristic, the 510(k) for the reprocessed-device must include performance data verifying that the worst-case effects of patient exposure, time, temperature, and humidity on all materials used in the device do not adversely affect its performance. Only after such an analysis is performed can the expiration date for the device be reset.

One OEM study of 10 balloon catheters, 20 diagnostic catheters, and 10 guiding catheters, all reprocessed, identified several packaging-related issues.⁴ Visual inspection revealed package-integrity, and thus sterility, problems with the balloon catheters. Several outer packages had openings or breaches that in some cases were large enough to admit the edge of a piece of paper through the seal. Package functional testing revealed channels in the inner and outer pouches of two samples that rendered the packages nonsterile. All outer-pouch seals failed a leak test and all inner-pouch seals failed a pull test to assess strength.

A similar study also focused on package integrity, employing visual observations as well as some functional testing. More than half of the 27 balloon, guiding, and diagnostic catheters tested exhibited some type of seal defect, including open seals. Specific failure rates were 59% for the package visual inspection, 63% for the package seal test, 26% for the package pull test, and 50% for the product visual inspection.⁵

Devices shipped to a hospital are subject to forces over which neither the hospital nor the reprocessor has control. Product packaging must therefore protect adequately against known and unknown traumas. In order to protect the integrity of the device, the reprocessor must understand the susceptibility of the device to harm and then design packaging that will guard against such harm.

Most delicate new OEM products are shipped in preformed packages designed to cradle the device and prevent kinks or defects from being introduced during shipping and handling. The same devices, after reprocessing, are often returned to hospital stocks in formless Tyvek pouches. But the adequacy of such packaging to protect the device must be demonstrated.

The packaging issues discussed here show that more than just product integrity data must be included in a reprocessed-device 510(k). Just as an original manufacturer would, the reprocessor must submit data that validates the packaging process used with the reprocessed device.

LABELING

Labeling questions pertinent to reprocessed SUDs include the following:

• How will the reprocessed-device label conform to FDA labeling requirements, including provision of adequate directions for use? How will the reprocessor be able to ensure that there is no misleading information or misrepresentation of the device's origin on the device or label?
• How will the OEM device label be obliterated so as not to mislead users into expecting the performance characteristics associated with the original device?
• What additional steps have been taken to ensure proper attribution of any device failure to the reprocessor rather than the OEM?
• How will the existence of natural rubber (latex) in a device's composition be detected so that appropriate user warnings can be included with the reprocessed device?

Data collected from hospitals indicate that current reprocessing practices fail to comply with even the most basic FD&C Act labeling requirements. In one study, reprocessed equipment from local hospitals was examined for proper part number, OEM name, dimensions, lot number, and extra wording that was to be placed on the outside of the reprocessed device. The investigators found that 90 of 213 devices were mislabeled (42%). In 77 cases, the incorrect dimensions were listed; 20 devices carried an incorrect part number; and the wrong OEM name appeared on 6 labels. Other errors that turned up included incorrect device descriptions, the addition of inappropriate phrases to the description of the device, and omission of a label, warning, or instruction for use.⁶

OEM labeling created for SUDs presupposes that the device will be disposed of and is therefore not designed to address its potential use history. Reprocessed-product 510(k)s must include labeling intended to advise the user more fully regarding handling, use, and inspection for wear of certain products. Only with appropriate labeling in place as a special control could reprocessed devices be considered equivalent to their OEM counterparts.

Proper identification of the reprocessor on the device label and associated printed information, as well as removal of any reference to the OEM, is necessary in order that the user not be misled and assume that the product is provided by the OEM. In the case of reprocessed devices from which the OEM label cannot be eliminated without sacrificing the device, the reprocessor must identify proper alternative methods for compliance to 21 CFR 801.1 and 801.6.

Physicians expect a certain performance profile from a particular device model and rely on the device to perform accordingly. Reprocessing-induced changes in the device may not be immediately evident. If the reprocessed SUD itself does not clearly indicate that it is not a new device, the physician may fail to alter his technique to compensate for material or other changes. For instance, reprocessing may reduce the temper of certain metals. A reprocessed device blade may initially be as sharp as a new device blade, but the reprocessed blade may grow dull more quickly, leading to unexpected performance degradation during use. Similarly, the change in stiffness noted with reused EP catheters would necessitate a change in technique by the electrophysiologist as the electrodes are manipulated into the area of the heart to be ablated. Just as FDA would require of an OEM device 510(k), such differences in product performance would have to be evaluated in comparison with the predicate device (that is, the original device) in order to support substantial equivalence.

Finally, as manufacturers of medical devices, reprocessors are subject to general controls, including the medical device reporting (MDR) regulation. Under this rule, both manufacturers of medical devices and user facilities are required to report a device-related death, serious injury, or malfunction to FDA within 30 days after becoming aware of the event. An error that often occurs is that inappropriately labeled reprocessed medical devices involved in MDR events are attributed to the OEM rather than the reprocessor. In cases where the reprocessed device has been altered to obliterate the OEM product label and a label identifying the reprocessor has been added to the device body, it is likely that a device involved MDR event will be identified as reprocessed. However, in instances where the OEM product label is not obliterated, the reprocessor must find a means for relabeling the device so that reports will identify the correct manufacturing source.

CONCLUSION

Important scientific issues raised by the practice of SUD reprocessing need to be addressed so that FDA premarket review of reprocessed-device submissions provides meaningful patient benefits. The answers to the kinds of questions posed in this article will be unique to each reprocessed-device model, and they are critical to an effective review of the relative safety and effectiveness of SUDs intended for reuse. The importance of answering these questions has been illustrated by citations of actual cases in which having such information in a 510(k) would probably have prevented defective products from entering hospital inventories.

The objective of this article was to establish a thought process that will be effective in identifying device-specific reuse issues during premarket review. The reuse of devices designed for a single use presents issues and challenges not presented by OEM devices. These issues must be carefully considered during premarket review so that neither the established regulatory system nor, more importantly, patient safety is compromised.

REFERENCES

1.Bruce Burlington, director, FDA Center for Devices and Radiological Health (CDRH), letter to Nancy Singer, special counsel, Health Industry Manufacturers Association, July 15, 1998 (FDA Docket No. 97P-0377).

2.Blue Book #k86-3: Premarket Notification Review Program (Rockville, MD: FDA CDRH, June 30, 1986).

3.SA Brown et al., "The Effects of Use and Simulated Reuse on PTCA Balloons and Catheters" (abstract presented at the Society for Biomaterials Sixth World Biomaterials Congress, Kamuela, HI, May 2000).

4.Report on Re-Furbished Single Use Devices (Miami Lakes, FL: Cordis Corp., December 1998).

5.Evaluation of Re-Furbished Single Use Devices (Miami Lakes, FL: Cordis Corp., October 1999).

6.Stryker Instruments (Kalamazoo, MI), letter to CDRH, April 10, 2000 (FDA Docket No. 00D-0053).

7.RL Fishman, "Letter to the Editor: Reuse of a Disposable Stylet with Life-Threatening Complications," Anesthesia & Analgesia 72, no. 2 (1991): 266–267.

8.Field Quality Engineering Report: Evaluation of Reprocessed Ethicon Endo-Surgery Single Patient Use (SPU) Devices (Ethicon Endo-Surgery Inc., October 1999).

9.Katherine Merritt, research biologist, Office of Science and Technology, CDRH, (statement presented at the FDA/AAMI Conference on the Reuse of Single-Use Devices, Crystal City, VA, May 5–6, 1999).

10.Prüfzentrum für MedizinProdukte, University of Tübingen, Examination of Devices Reprocessed by Vanguard, Declared to be Sterile (Tübingen, Germany: University of Tübingen, March, 2000).

11.Letter from Birmingham Baptist Medical Center to CDRH (October 19, 1999).

12.R&D Report: Changes in Electrophysiology Catheters during Reprocessing and Reuse (Biosense Webster, October, 1999).

David L. West, PhD, LD, is vice president of Quintiles Consulting (Rockville, MD) and served as deputy director in the Office of Device Evaluation at CDRH from 1989 to 1993. Timmie Topoleski, PhD, is an associate professor of mechanical engineering specializing in biomaterials and biomechanics, and director of the Laboratory for Implantable Materials at the University of Maryland Baltimore County. William MacFarland is a consultant with Quintiles Consulting, and served as a reviewer in the Office of Device Evaluation. Funding for this article was provided by the Association of Disposable Device Manufacturers.