When the biological evaluation of medical devices is approached as a routine function involving nothing more than successfully passing a series of biocompatibility tests, there is little opportunity for innovatively managing positive test results, which indicate that a material is toxic. But blind compliance is not the intent of the International Organization for Standardization (ISO) or FDA.13 Manufacturers have the freedom, and the responsibility, to apply the ISO biological evaluation standard in a way that ensures the biological safety of their devices while conservatively managing resources. Neither ISO 10993-1 nor the FDA memorandum on its use specify pass/fail criteria for biological testing, recognizing that it is almost impossible to set general criteria and that manufacturers are in the best position to determine what level of toxicity is acceptable for their products.
Based on careful comparisons of biocompatibility and clinical data, some companies have determined the highest safety test score relating to unacceptable performance for a specific class of products and use this value as the pass/fail criterion. At many companies, however, there is a tendency to panic when biological safety test results are positive. The possibility of a positive result can call into question carefully considered material choices, threaten costly delays in product development schedules, and raise doubts about test strategies. Manufacturers may hastily pursue many directions at once, ending with an array of conflicting information. Or they may forget that the goal of biological safety testing is to determine whether a material or device is safe for its intended use, and not (necessarily) to determine the cause of toxicity.
The best approach to any situation where the ideal may be unobtainable is to follow a planned course of action, first confirming the facts at hand, then considering the options for future actions. Applied to the problem of positive biocompatibility test results, this means methodically confirming that the test procedure was followed as intended and that the test result is reproducible, and then considering whether the toxicity can be eliminated or is acceptable (see Figure 1). The steps in this strategic approach are described below.
CONFIRMING THE TEST PROCEDURE
Confirming that the positive test was carried out according to the specified procedure requires an investigation of several points. If the test was conducted according to good laboratory practices (GLPs), the signed test protocol can be examined for possible sources of error.4 In many cases, however, the standard protocol may be quite brief, and a closer look at study details will be necessary. If the test was not conducted per GLPs, as is the case for many 510(k) devices, the following questions can be used as a guide.
Was the Correct Test Article Evaluated? Mix-ups regarding the samples supplied to a testing laboratory are more likely in the early stages of product development programs, when several similar materials are being screened. Old lots of materials may have deteriorated or similar-looking materials that were stored near the intended sample materials may have been erroneously sent out for testing. Of course, there is always the possibility that the testing laboratory mixed up some samples upon receipt. The manufacturer should insist that the laboratory review its log sheets to confirm exactly what was tested.
Was the Correct Formulation Evaluated? Formulations such as those for wound dressings, electrode gels, bone cements, or dental fillings are likely to go through many iterations, and many will fail performance testing before safety testing is even undertaken. When several candidate formulations are in process, it is easy to unintentionally send one out for testing. It is also possible that errors were made during formulation. For example, when an electrode gel formulation had a surprisingly positive test result, subsequent analysis showed that the formulator had inadvertently added the wrong kind of potassium salt, raising the pH and preparing a highly corrosive material.
Was the Test Article Manufactured Correctly? Manufacturing processes that can affect safety test results can be categorized into three groups: those that alter a material mechanically; those that potentially introduce, or are intended to remove, chemical entities; and those that alter the surface chemistry of the test material. When a positive test occurs, the manufacturer needs to determine whether mechanical processes have introduced configuration anomalies, whether chemical processes have introduced or failed to remove toxic moieties, or whether energy processes have introduced surface changes, any of which may have an unexpected and untoward effect on material biocompatibility.
Mechanical processes such as stamping and die-cutting can introduce sharp burrs or edges on devices, which secondary processes such as polishing and burnishing are intended to remove. If a processing problem occurs and the sharp burrs or edges remain, they can cause skin irritation when whole test articles are applied to an animal, or cause cell damage or death when applied directly to cells in cytotoxicity tests.
Many processes that introduce new chemical entities, such as epoxy glue, or that remove chemical entities, such as organic cleaners, can also affect test results. Medical tapes present a good example: During manufacturing, tapes are passed through large ovens to evaporate and remove organic solvents trapped in the adhesives. If the tapes pass through the oven too rapidly or if the oven temperature is too low, some residual solvents may remain, resulting in an intrinsically toxic product.
Finally, other manufacturing steps can alter the chemical structure of the test material by breaking and reforming organic bonds. Ion implantation to increase lubricity or alter other surface properties is one example. Gamma and electron-beam sterilization, which bombards products with high-energy radiation or electrons, is also likely to alter the material surface, and sterilization with ethylene oxide creates by-products that may absorb into the material surface.
Was the Test Article Clean? Although all device manufacturers recognize the importance of supplying clean, sterile products to their customers, sometimes the same high level of respect for cleanliness is not provided for test articles. A material may be sent for testing as received from the supplier, without any concern for its state of cleanliness. In other cases, a test article may have been handled with ungloved hands or laid on a desktop, risking exposure to food or erasure crumbs. It is critical that designers place test articles in appropriate packaging and never handle them directly.
Was the Test Article Properly Identified? The distinction between product and packaging is usually clear to the manufacturer, but not always to the laboratory, which may inadvertently extract both packaging and product to prepare the test sample. The test article should be clearly identified, such as "a guidewire shipped in polyethylene-tube packaging," and the sample preparation instructions should clearly state that the packaging is to be discarded prior to extraction.
Was the Test Article Stored Properly? Some materials must be stored frozen, humidified, dehumidified, or away from light. Test articles should be properly packaged to optimize storage conditions and clearly labeled to communicate storage requirements to the laboratory.
Was the Correct (Intended) Extractant Used? Because the nature of the extractant can have a profound effect on safety test results, specific extractants may be necessary for certain types of products. For example, a drug excipient may be the preferred extractant for materials used in drug-delivery devices, artificial saliva may be preferred for dental devices and artificial perspiration for electrode gels, and a minimal essential medium containing serum that mimics wound exudate might be preferred for wound dressings. The test laboratory should confirm that the specified extractant was actually used.
Were the Correct (Intended) Extraction Conditions Used? Many new materials behave differently than traditional ones; superabsorbers, for example, obviate the usual rules relating to volume of extractant per gram or surface area of material extracted. Following traditional extraction ratios for such materials will result in a sample as viscous as syrup, which may cause instantaneous death when injected into mouse tail veins (the result of myocardial infarction as the injected sample travels as a bolus directly to the heart). Extraction conditions should be developed specifically for a new type of material and used consistently throughout the product history.
Was the Protocol Followed? If a test is carried out under GLPs, any deviation from the protocol should be documented, but deviations must be recognized to be recorded and custom protocols may contain procedures unfamiliar to the laboratory technicians. For example, materials such as casts and dental cements are cured in situ, with curing beginning as soon as the packaging is broken and the components mixed together. Breaking open the package and mixing the components are critical steps in sample preparation but outside the normal routine of the technician. Compliance with such unusual steps in a protocol should be examined carefully if test results are variable or other than what was expected. If the laboratory's standard protocol was used rather than one customized for the test material, this protocol should be reviewed carefully to ensure that it does not contain procedures that are incompatible with the testing requirements of the article in question.
In addition to addressing these questions, the manufacturer should ascertain from the testing laboratory whether the results of positive and negative controls included in the test run were normal, and whether there were any unusual results observed in the test run as a whole. The test procedure is considered confirmed if nothing in the investigation indicated a deviation from what was intended when the test was ordered. Obviously, if the intended procedure wasn't followed, the test should be repeated correctly.
CONFIRMING RESULT REPRODUCIBILITY
The next step in the strategic approach to managing a positive safety test result is to confirm its reproducibility. There is a tendency for companies to simply send out a duplicate test article with the notion that if the result is again positive, the material is indeed toxic, but if the result is negative, the material is safe. There's a fundamental problem with this thinkingwith only one positive and one negative test result, which can legitimately be believed? On the other hand, manufacturers can create problems by testing too many articles with too many variables at too many laboratories. The sometimes-positive, sometimes-negative outcomes result in conflicts that may require expensive research projects to resolve. In spite of conformance to standard test methods, each different laboratory used will introduce new variables to a test. It can be very difficult, if not impossible, to sort out why a material passes a test at one laboratory and fails the same test at another.
The middle road is to submit two additional test articles to the original laboratory. The two test articles should be separated from each other and the original sample by time and space; for example, they might be from separate manufacturing lots, made on separate days, taken from the start and end of a run, or made by separate shifts. The test articles should be identical to each other and the original article in all other aspects of composition and the manufacturing process. The results of the additional tests can be considered to either confirm or deny the toxicity of the original test article. Product development can usually proceed if the results of two out of three tests are negative.
It is important at this point to remember the purpose of the additional testing. Analysts may be tempted to embark on a series of experiments, testing various formulations or methodically eliminating one ingredient or process at a time, in order to pinpoint a causative agent. But the goal in this second step is simply to confirm the reproducibility of the result, not to investigate its cause.
If the toxicity of the material is confirmed by repeated testing, the ideal solution is to eliminate the toxicity. If the test article is a formulation or assembly, or is subjected to manufacturing processes, any one ingredient or process step may be causing the positive test result. Thus, the next step in the management process is to identify the causative agent.
The manufacturer should begin this investigation by reviewing all the information available regarding the test article's components. There may be clues to a toxic moiety in the drawings, material safety data sheets, vendor technical sheets, or chemical formulation. For example, one vendor added a cadmium stabilizer to a rubber formulation without directly informing the manufacturer. In another case, a job shop added a rigid material to the interior of a tube to stabilize the structure, which the manufacturer discovered when the device was cut in half to generate a drawing. If toxicity was observed with whole devices but not with extracts, the configuration may be the cause of the problem.
The available information regarding the manufacturing processes should also be reviewed. Could the chemical or energy processes used in the manufacture of the test article be contributing, creating, or incompletely removing toxic moieties? The lot history record of the test article should reveal whether anything unusual happened during this particular manufacturing run.
Finally, the manufacturer should seek out new information. A literature search on the key components in the test article may reveal whether any of them have a history of toxicity. Obtaining infrared profiles with an isopropyl alcohol extraction before and after processing can determine processing effects.5 Discussing test results with the material supplier is also important. Very frequently a supplier knows why a material may fail biocompatibility testing.
Once the information review has pinpointed the cause of toxicity as closely as possible, then one or more of the following changes can be implemented to eliminate toxicity.
- Use different ingredients or a different ratio of ingredients to obtain a formulation that is not toxic. It may be possible to reduce the percent contribution that a particular component makes to the total formulation, or to use an alternative ingredient.
- Improve quality control measures for mechanical process steps to ensure that burrs and sharp edges are not introduced or allowed to remain.
- Make changes to the manufacturing process that eliminate the addition of toxic contaminants or ensure the complete removal of existing contaminants. For example, solvent solutions used to clean metal parts must be completely removed and the coagulant used to precipitate latex onto mandrels must be thoroughly washed away.
- Replace a material with another that can serve the same function without contributing to toxicity. This is frequently possible when the material functions more or less independently within the product design.
Although eliminating toxicity is the ideal, there are situations where this is not possible. Toxicity may be intrinsic to the product and impossible to eliminate without compromising product function. One familiar example is the electronic componentry of pacemakers and cochlear implants. The toxic circuitry in these devices must be contained within a nontoxic case so it cannot leach out and injure the implant recipient. Another example is a simple product called an adhesive remover. No matter how it is formulated, the product is always a mixture of organic solvents that carry with them the possibility of systemic toxicity subsequent to skin absorption.
Medical devices that must cure in situ are also intrinsically toxic. The curing process of products such as casts, dental cements, and bone cements may involve the generation of free radicals or other reactive chemical moieties, or may be exothermic. In addition, implants made from nickel alloys carry an intrinsic level of toxicity. Nickel is a cardiac toxin, an oxytocic agent, and a common sensitizing agent (an estimated 5% of the population are allergic to nickel contact).6 The possibility of nickel being released into the biological environment always poses the risk of toxic response.
There are also some devices whose functions result in injuryfor example, a medical tape designed to hold an appliance onto the skin. If the appliance is life-supporting, the tape will be expected to adhere to the skin with some high degree of tenacity so that the device will not fall away. This high adhesion level is likely to result in skin injury when the tape is ultimately removed.
In each of these examples, the toxicity is intrinsic to the device: Suitable (nontoxic) alternative materials do not exist, or the device will not function as intended if the injurious material is removed. The manufacturer is left with no alternative but to accept the toxic material. The strategy becomes one of justifying its use.
Justifying Use of the Material. There are three approaches to justifying the use of a toxic material in a medical device. The first is to compare the level of toxicity of the material to a comparable material that is currently being used by the manufacturer. If the new material has a lower level of toxicity than the current one and the current one has a safe history of use in the marketplace, the use of the new material may be justified because it is a move in the direction of decreased toxicity and increased biological safety.
The second approach is to compare the level of toxicity of the material to a comparable material that is currently being used in a competitive product. Again, if the new material has a lower level of toxicity than the competitive material in the same biological safety test, and the competitive material has a safe history of use in the marketplace, the use of the new material may be justified.
In the third approach the maximum dose and the no-observable-adverse-effect level (NOAEL) for the material are calculated and then compared.7 To determine the level at which no adverse effect occurs, the sample is titrated by using decreasing amounts in the test system. The highest concentration of sample at which no effect is observed is the NOAEL, which can be expressed in units, surface area, weight, or volume of material. The maximum dose of a material equals the units, surface area, weight, or volume of material to which a patient will be exposed during a typical course of therapy. If a material's maximum dose is 100-fold less than its NOAEL, the material is considered safe for use. (The 100-fold criterion is based on a 10-fold variation between species and a 10-fold variation within species.) The comparison must be repeated for each biological safety test giving a positive response.8
The NOAEL approach has been employed to justify the use of nickel alloys in implants. The amount of nickel released by in situ corrosion is compared with the maximum permissible amount of nickel that can be given per day in intravenous fluids, which was determined from intravenous injection of nickel in dogs.6 If the release of nickel through corrosion is less than the amount that can be safely given in intravenous fluids, the alloy is considered safe for implantation.
Dealing with Risk. Accepting a level of toxicity in a medical device carries with it some level of risk to patients. A responsible company will want to assess this risk level and determine whether or not the benefits of the device outweigh it.
Many devices that pose biocompatibility risks have become widely accepted because of their benefits. For example, a certain percentage of the population will experience life-threatening anaphylactic shock from the contrast media that is injected in preparation for x-ray. Nevertheless, since suitable alternatives do not exist, the medical community judges the potential benefits of the procedure to outweigh the risk. Another example is implantable heart valves, where thromboembolism is the most feared adverse effect. Thromboembolisms occur in about 3% of patients who receive mechanical heart valves, a percentage that is deemed the standard risk.9
To determine the risk/benefit ratio for a new product, the positive biological test result that identified its toxicity must be related to an actual effect that might take place in a patient using the device. For example, is the potential effect cardiac arrest, sensitization, or skin irritation? What will be the outcomeduration, level of pain, and degree of disablementif injury occurs to a particular patient? What expenses will there be for the patient, both in medical costs and in loss of income? If the severity of the risk is considered to be the sum of some dollar value placed on the effect, the associated expense, and the expected outcome, a value for severity can be calculated using the equation:
Then, by estimating the frequency of the effect for the patientwill it be a single occurrence or will the injury be repeated with each use of the device?risk can be calculated as the product of the severity level and frequency:
Placing a monetary value on the risk provides a numerical way to compare it to the product's benefits. Of course, if the risks to patients are morally unacceptable or are not outweighed by the benefits of device use, the manufacturer should refrain from offering a device for sale.
Any manufacturer that wishes to stay in business will also want to assess the risk to the company in the event of injury to patients. In this case, the applicable equation is:
|Risk =||(Loss of sales) + (Loss of goodwill)|
|+ (Cost of legal action × Number of suits)|
|+ (Cost of recall × Likelihood of recall)|
One author has estimated the cost of a recall to range from $200,000 to $500,000, with an average cost of $300,000.10 Monetary values can easily be assigned to the other considerations, too, to derive a value for company risk. A high risk value that will not be outweighed by product sales should dissuade the manufacturer from offering the device for sale.
Similar analyses can be applied in order to calculate a risk to any other entity or person. In some cases, a manufacturer might want to estimate the risk to the environment, the risk to caregivers, the risk to hospitals, or the risk to other third parties.
Labeling for Safety. Every manufacturer should have a mechanism for reviewing product labeling for its consistency with device biological safety. Specifically, the directions for use, package inserts, and advertising should be reviewed. Some departments within the company may deem this unnecessary and observe that it lengthens the product development phase, delaying market entry. However, without a system of checks and balances some very strange claims can creep into product labeling. Clear, unambiguous labels are critical for devices that have potentially toxic effects.
Finally, whatever strategic approach and ultimate decisions a company makes with regard to managing biological safety testing, it is important to be logical, defensible, and consistent in decision making. The justification for accepting a toxic material must be based on sound physical, chemical, immunological, biological, and analytical principles. Any deviations from standard practice, FDA memorandum G95-1, or ISO 10993-1 should be documented and filed. And decisions should be applied consistently across the product line and across company functions.
1. "Biological Evaluation of Medical DevicesPart 1: Guidance on Selection of Tests," ANSI/AAMI/ISO 10993-1:1994, Arlington, VA, Association for the Advancement of Medical Instrumentation (AAMI), 1995.
2. "Use of International Standard ISO-10993, 'Biological Evaluation of Medical Devices, Part 1: Evaluation and Testing,'" Blue Book Memorandum G95-1, Rockville, MD, FDA, Center for Devices and Radiological Health (CDRH), Office of Device Evaluation (ODE), 1995.
3. Seidman B, "Manufacturer Use of ODE's Blue Book Memorandum on Biocompatibility Testing," Med Dev Diag Indust, 18(6): 5866, 1996.
4. Code of Federal Regulations, 21 CFR 58, "Good Laboratory Practices for Nonclinical Laboratory Studies."
5. Wallin R, "In Vitro Testing of Plastic Raw Materials," Med Dev Diag Indust, 15(5): 126132, 1993.
6. Sunderman FW, "Potential Toxicity from Nickel Contamination of Intravenous Fluids," Ann Clin Lab Sci, 13(1):1, 1983.
7. Ecobichon DJ, The Basis of Toxicity Testing, Boca Raton, FL, CRC Press, 1992.
8. "Method for the Establishment of Allowable Limits for Residues in Medical Devices Using Health-Based Risk Assessment," AAMI/ISO/CD-V 14538, Arlington, VA, AAMI, 1996.
9. "Draft Replacement Heart Valve Guidance," Appendix K, Rockville, MD, FDA, CDRH, Div. of Cardiology, Respiratory, and Neurological Devices, 1994.
10. Wood BJ, and Ermes JW, "Applying Hazard Analysis to Medical Devices, Part II: Detailed Hazard Analysis," Med Dev Diag Indust, 15(3):5864, 1993.
Nancy J. Stark is a Chicago-based consultant specializing in medical device biological safety and clinical research. This article is based on a portion of her book, Biocompatibility Testing & Management, 2nd ed, Chicago, Clinical Design Group, 1996.
Figure 1. Flowchart of steps to be followed in managing positive biocompatibility results.