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PARAMETRIC RELEASE COMES TO ETO STERILIZATION

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published February 1996

Paul J. Sordellini

After decades of anguishing over long aeration times and interminable incubation periods, manufacturers of medical devices sterilized with ethylene oxide (EtO) may finally be getting something of a break. Thanks to the efforts of industry experts in the United States and abroad, significant attention is now being paid to the possible use of parametric release for EtO-sterilized devices. Their work is providing industry with safe and complete guidance that may soon make parametric release an everyday reality. As a result, companies can expect to see a dramatic improvement in the turnaround times for products sterilized in-house or out sourced to contractors.

It is estimated that approximately 45% of the medical devices manufactured in the United States are sterilized using gamma irradiation. Another 45% of the market is claimed to be held by EtO, while the remaining 10% is held by steam and electron beam (E-beam).

When using any of these four sterilization methods, manufacturers must validate the process in order to provide documented evidence that it will consistently yield the desired sterility and sterility assurance level (SAL). Upon completion of all stages of validation, routine control procedures for gamma, E-beam, and steam consist of monitoring the physical parameters of the process. Products may be released as soon as it has been confirmed that the routine production cycle has fallen within the parameters established during validation. For gamma and E-beam those parameters are exposure time and absorbed dose; for steam, they are exposure time and temperature. In either case, the time required before products can be moved out of the poststerilization phase and shipped to market is generally dictated by the time necessary to perform a routine quality assurance review of the physical process parameters verified during the sterilization cycle. Release of products on this basis is called parametric release.

While parametric release is the norm for most sterilization methods, however, it has rarely been employed by contract EtO sterilizers. Following completion of an extensive validation process, EtO sterilizers have continued to use biological monitoring during routine production cycles as the basis for product release. The typical process used for EtO sterilization includes initial inventory control checks, placement of biological indicators (BIs), preconditioning, time inside the sterilization vessel, aeration, retrieval of BIs, shipment of BIs to the testing laboratory, BI preparation, as many as seven days of BI incubation, compilation of the test result report, and communication of test results to the manufacturer--who can only then arrange return shipment of the lot to the manufacturing site for inspection and distribution. In some cases the resident time of a given product lot within the walls of a contract EtO facility can be as long as 11 days, and it can be even greater if weekends intervene to hinder BI preparation or retrieval.

Just as the practice of parametric release by EtO contractors has been rare, so has been the availability of related guidance documentation. The 1988 standard compiled by the Association for the Advancement of Medical Instrumentation (ANSI/AAMI ST27) dedicated only one brief paragraph to the subject of "process control release," stating that if controls are sufficiently reliable, process control release may be considered.1 The absence of further detail-- together with the accompanying note that regulatory authorities such as FDA may have to grant their approval for process control release--undoubtedly prevented many EtO sterilizers from seeking to use this technique.

In 1994, U.S. delegates voted to adopt a newer standard compiled by the International Organization for Standardization (ANSI/ AAMI/ISO 11135) in place of ANSI/AAMI ST27.2 This document contains updated ISO-compatible requirements for validation, control, and conventional BI-based release of EtO-sterilized product. But it goes beyond earlier standards by including a full section on parametric release, which details what needs to be done differently during validation and routine control in order to release product parametrically. Annex D of the standard is also devoted to this subject and furnishes specifics regarding management expertise, temperature spread across the load, monitoring of effective recirculation, and performance qualification. In the hands of a sterilization expert, ISO 11135 offers enough information for a contract sterilizer to begin instituting parametric release and, in fact, industry interest in this time-saving system has increased dramatically.

THE POTENTIAL OF PARAMETRIC RELEASE

The use of EtO for sterilization is as old as the equipment commonly employed. Parametric release of devices processed with gamma radiation, E-beam, and steam is also an old practice. However, because EtO sterilization requires accurate control of a greater number of variables--thus making it somewhat of an art rather than a pure science--industry has preferred to continue using BIs to confirm the successful integration of all the critical parameters. In this context, the routine use of parametric release would represent a significant advance in the field of industrial EtO sterilization for medical devices.

The present push toward making parametric release a routine part of the world of EtO sterilization is the result of two forces. First, by adopting ANSI/AAMI/ISO 11135, industry finally has an internationally recognized document that lists the general requirements for parametric release. Second, to keep up with the trend of cost cutting that is affecting all sectors of the health-care marketplace, the medical device industry has a desperate need for greater efficiency in all its processes.

One response to the need to reduce health-care costs has been to eliminate massive stockpiles of medical products and switch to just-in-time (JIT) inventory systems. This changeover applies both to hospitals, which now order only what they need and only when they need it, and to manufacturing companies, which now regulate their production according to immediate market demand. To implement a JIT system, the manufacturing sector must upgrade its ability to respond efficiently to periods of increased market demand for its devices. For many device manufacturers this has meant switching to gamma, E-beam, or steam sterilization, where the opportunity to use parametric release translated into quicker response time and reduced costs. But for other manufacturers whose devices suffer from material incompatibility with those methods, EtO has remained the only viable sterilization option. And with it has come long turnaround times and limited flexibility in responding to market demands.

The technique of releasing EtO-sterilized product based on process parameter review has the potential to revolutionize the EtO industry. Once validation of the process has been completed, use of parametric release will streamline the EtO sterilization process to initial inventory control checks, preconditioning, sterilization, and aeration, followed by direct shipment to distribution sites. Allowing a few hours for initial and final inventory control, and 12 hours each for preconditioning, sterilization, and aeration, it is conceivable that a product lot could enter and exit an EtO sterilization facility in about 40 hours--thus rivaling the turnaround times offered by other sterilization methods. Other products may require more time, depending on their resistance to the process, vacuum sensitivity, and aeration requirements.

Added advantages of parametric release are less product handling and related damage. Many manufacturers have experience with the damage and delays associated with cutting open boxes to place BIs, reopening the same boxes after processing to retrieve the indicators, lost or incorrectly placed BIs, and laboratory errors in handling or incubating BIs. There is also the expense of purchasing, placing, retrieving, and testing the BIs to consider. In addition, once a contract sterilizer has handled a product lot so extensively, manufacturers usually require that the load be returned to the manufacturing site for a careful quality inspection.

By contrast, a load that is going to be released parametrically can be net wrapped by the manufacturer and processed without ever having a single carton removed or opened. Net wrapping permits temperature probes to be inserted between cartons at sites appropriate for monitoring validated temperature parameters. The load can then remain intact throughout the sterilization phase and be confidently shipped from the sterilization site directly to a distribution center--thus avoiding the time and expense of bringing it back to the manufacturer. In harmony with JIT, some manufacturers could have products EtO-sterilized and on their way to market less than 48 hours after they come off the assembly line.

To be sure, implementation of parametric release will require EtO sterilization firms to make substantial financial and professional commitments. The costs of installing and operating the additional gas analysis equipment required for parametric release can be considerable. Company management will require additional training, validation protocols will have to be reworked, and standard operating procedures will need to be upgraded. And, most important, the company will need to establish clear and efficient channels of communication with its customers, so that all parties can review the process data before the end of the aeration phase, thereby taking full advantage of the potential for timely product release.

For manufacturers, there may be a slight disadvantage to the implementation of parametric release, since EtO sterilizers may seek to recoup the costs of their new equipment by charging higher fees for each load released parametrically. On balance, however, the benefits of parametric release should justify these charges, which should contribute to the overall reduction of health-care costs.

AAMI'S TIR

A key element in the movement toward parametric release of EtO-sterilized products was put in place at AAMI's June 1995 meeting in Washington, DC, where three task groups were formed for the purpose of writing a technical information report (TIR) concerning various parts of ISO 11135. One of these groups is dedicated to writing a report on the engineering aspects of industrial EtO sterilization, which will include a section of complete guidance for anyone intent on initiating parametric release of EtO-sterilized devices. As currently conceived, this section is expected to discuss requirements for equipment, validation, routine controls and monitoring, release of product, and contract sterilization.

A first draft of the entire TIR--including the section on parametric release--was presented for committee review at another AAMI meeting last September. While there is still a great deal to be discussed--and the document is sure to undergo many more changes before final presentation to the full committee--it is not too early to discern some of the key issues related to parametric release now under discussion.

The September draft of the TIR stresses the importance of ensuring even distribution of moisture and sterilant, and emphasizes the need to monitor the actual functioning of recirculation systems during the preconditioning, sterilization, and aeration phases. In a related discussion, members of the task group questioned the recommendations of ISO 11135, Annex D (an informative appendix, and therefore not part of the standard's requirements), which suggests that product temperature across the load be permitted to vary only 3°C (5.4°F) above the minimum acceptable validated temperature. This means that if the sterilization cycle is validated to a run at a minimum of 120°F, the product temperature spread across the load should be controlled to a range of 120°­125.4°F in order to satisfy the requirements for parametric release. Such a tight temperature range is realistic provided that the sterilization vessel is small, but members of the group noted that achieving such a tight product temperature spread in large industrial vessels would render parametric release prohibitively expensive or even impossible. As an initial solution, the task group proposed that its draft recommend a slightly higher acceptable temperature spread than that suggested by ISO 11135, Annex D. Whether this proposal will withstand further discussion remains to be seen.

Other issues of importance include product load configuration and the presence of "cold spots" within the load. Because a lower-than-validated product temperature would compromise the SAL delivered by the process, all members of the task group agreed that the minimum specified product temperature must be validated, maintained, and monitored at all times. But there was disagreement over the question of whether the product temperature range specified by previous standards (AAMI ST27 accepted a range of 18°F) needed to be narrowed for parametric release. Those favoring a less restrictive range reasoned that only the minimum temperature needed to be defined in order to ensure the product's SAL; the maximum temperature need only be governed by the thermal sensitivity of the product and packaging. Since higher temperatures accelerate and benefit the sterilization process, they should not be discouraged unless the product or packaging integrity are at risk. Although this question is yet to be resolved, one proposal was for the TIR to require only that the load be kept above the minimum validated temperature, without specifying a particular product temperature range.

Because product load configuration is an important element in the success of parametric release, the AAMI task group determined that manufacturers should be given more guidance on this subject than has previously been available. In the case of a load made up of only one type of product, it often happens that a certain location inside the vessel consistently yields lower temperatures. Such cold spots are typically found in pallets placed next to sterilizer doors, and may be due to recirculation factors affecting that particular area. In such cases, the group agreed that it is essential to identify such cold spots during the validation phase (using both empty-chamber qualifications and product/process validation cycles), and that additional probes be inserted in these locations during all routine production cycles.

In the case of loads made up of many different products (i.e., custom kits) the committee insisted that there be clear guidance regarding the management of cold spots. The validation should be engineered in such a way as to identify not only "fixed" cold spots (consistent with sterilizer location), but also "wandering" cold spots that originate from the presence of certain types of product within the load. Although the nature of the TIR's guidance is not yet determined, one proposal is to require that manufacturers conduct a comparative thermal study of all items composing the product family in order to determine which products show slow heat absorption or poor heat retention. Subsequent validation would then be engineered to include a worst-case load configuration of products deemed to be the most difficult to heat. Later, if a routine processing configuration contained a significant number of these worst-case products, additional temperature probes would be used to ensure compliance with the minimum validated temperature.

CONCLUSION

It is expected that the AAMI TIR will be published sometime in 1996, and it will be interesting to see how the document develops and what effect it will ultimately have on industry. Parametric release is not the only subject dealt with in the engineering TIR. Guidance will also be provided for all equipment necessary for proper EtO sterilization, for methods of calculating the relative humidity inside a vessel, and for dealing with issues of process equivalency among multiple vessels. There are many other ideas that may find their way into the document or into practice:

* Using a period of conventional product release with extensive temperature probing in order to accumulate thermal profiles of diverse product lot configurations.

* Employing various methods of gas analysis (flame ionization detector gas chromatography, Fourier-transform infrared spectroscopy, microwave molecular rotational spectrometry).

* Employing various methods of moisture analysis (electronic humidity sensors, thermal conductivity detector gas chromatography, Fourier-transform infrared spectroscopy, microwave molecular rotational spectrometry).

* Implementing a required frequency for headspace analyses (e.g., once at the beginning and once at the end of dwell, at five-minute intervals during the entire dwell).

* Requiring sterilizers to correlate calculated gas and moisture measurements with those verified through direct analysis.

* Establishing the need to monitor and control the quality of steam used during the conditioning phase.

The ultimate evolution in modern EtO sterilization of medical devices, however, is still some way off. This will come when routine parametric release is combined with in-chamber dynamic environmental conditioning, a process that bypasses the time-consuming phase of external preconditioning. When that practice becomes routine, products that are able to withstand a deep vacuum cycle will be transferred directly from the truck to the vessel, sterilized, aerated, and shipped to market--sometimes in less than 24 hours. The current developments in EtO sterilization are a small step forward along the path to such a future.

REFERENCES

1. Guideline for Industrial Ethylene Oxide Sterilization of Medical Devices, ANSI/AAMI ST27, Arlington, VA, Association for the Advancement of Medical Instrumentation (AAMI), 1988.

2. Medical Devices--Validation and Routine Control of Ethylene Oxide Sterilization, ANSI/AAMI/ISO 11135, Arlington, VA, AAMI, 1994.

Paul J. Sordellini is a sterilization consultant with Quality Solutions, Inc. (Annandale, NJ).

DESIGNING CLINICAL TRIALS

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Gerard J. Prud'homme

For more specific information on clinical trials, refer to the topics below:

From the enactment of the Medical Device Amendments in 1976 to the early 1990s, more than 600 medical devices were cleared to market through FDA's premarket approval (PMA) process. Only a very small number of these PMA applications relied on data from randomized clinical trials. Throughout that period, FDA's Center for Devices and Radiological Health (CDRH) accepted as common practice the use of historical controls in support of applications for medical device approval. In the past two or three years, however, CDRH has taken significant steps toward imposing more stringent requirements on clinical trials used in support of PMA applications, and clinical studies are now required much more frequently to support 510(k) applications.

Why has the randomized clinical trial recently become the reference standard for medical device clinical studies? One response is that the device industry needed to catch up to the requirements of good science, and that such trials offer the only way to control selection biases among treatment groups. A more jaundiced view is that the push for randomized clinical trials is principally an infusion of "drug science" into device clinical studies. The truth probably lies somewhere between these two views.

In the evolution of device clinical trials, 1993 was a watershed year. It was in March of that year that the "Final Report of the Committee for Clinical Review," commonly known as the Temple report, was issued.1 That report described a pattern of deficiencies in the product applications the committee had reviewed, and identified lack of attention to basic study design as the fundamental flaw. The report concluded that the deficiencies were so serious as to impede the agency's ability to make judgments about the safety and effectiveness or substantial equivalence of the devices described by the applications.

Notably, the Temple committee was overwhelmingly composed of physicians and biostatisticians from FDA's Center for Drug Evaluation and Research (CDER); hence the beginning of "drug science" in-fluence in 1993. Bruce Burlington, who was appointed director of CDRH that year, had spent the previous five years as deputy director of CDER's Office of Drug Evaluation II. Later in the year, Susan Alpert, who had previously been a medical officer at CDER, became acting director (and later director) of the device center's Office of Device Evaluation (ODE). Both Burlington and Alpert are strong proponents of well-designed clinical trials to answer questions about the safety and efficacy of investigational devices.

In a speech on March 31, 1993, Burlington commented that "the Temple report is not an indictment of the past, but a consideration for how we might do things in the future." Later that year, CDRH issued a more definitive statement about the future in a draft document entitled "Medical Device Clinical Study Guidance."2 The intent of that document was "to instruct sponsors on clinical trial purpose and process" and to provide "the elements of good clinical study design, conduct, and analysis." Through the guidance, FDA made it clear that randomized clinical trials would be the wave of future device studies. In the section on study design, for example, the document states: "Other methods of treatment assignment can be devised . . . but, unless an explicit randomization scheme is used, it is difficult to ensure that the resulting assignments are free from . . . possible biases."

To promulgate the message of the draft guidance, FDA cosponsored a videoteleconference, "The Principles of Good Clinical Study Design," in January 1994. In early 1995, CDRH issued a draft document, "Clinical Trial Guidance for Non-Diagnostic Medical Devices," which reiterated many of the principles stated in the September 1993 guidance document.3 Indications are that the agency is planning to release other clinical study guidances, including one for in vitro diagnostics.

Taken together, these developments demonstrate that the device center's perspective on what constitutes good science for medical device clinical studies has changed dramatically in the past few years. The emphasis on randomized, blinded studies and a bias against the use of historical controls have seemingly become preferred ODE policy.

The design of modern medical device clinical studies must be set in the general context of good clinical practices (GCPs) guidelines that have developed substantially over the past two or three decades. Although the World Health Organization issued a guidance document on GCPs several years ago, FDA's version of a GCP guidance is of much more recent vintage.4 In August 1995, the agency published a draft "Guideline on Good Clinical Practices" under the auspices of the International Conference on Harmonization (ICH).5 The objective of the ICH guidance is to provide a unified standard that will facilitate mutual acceptance of clinical data by regulatory authorities in the United States, the European Union, and Japan. The document defines good clinical practice as an international ethical and scientific quality standard for the "design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected." FDA's CDER and Center for Biologics Evaluation and Research were among the six ICH sponsors.

The ICH guidance describes 13 basic principles ranging from the premise that all clinical trials should be conducted in accordance with well-accepted ethical principles to the notion that quality assurance should be built into all aspects of the study (see box, this page). Although CDRH was not a sponsor of this document, it is likely that the device center will pay close attention to these guidelines as future medical device clinical studies are evaluated.

Because the scientific integrity of a clinical trial and the credibility of its data depend substantially on the design of the trial, FDA's investigational device exemption (IDE) regulations require sponsors to submit an investigational plan for any clinical study involving a significant-risk device. The most important element of such a plan is the study protocol, which details all components of the proposed study.

The study protocol should be designed to address all of the basic questions to be examined by the investigation. These include the specific objectives of the study, the controls to be used, the number of patients to be enrolled, the type of masking to be used, what follow-up information will be collected, and many other issues. Taken together, the essential elements of a study protocol form a unified plan to address all such questions in order to determine whether the investigational device has a particular clinical effect. As described below, these essential elements are well recognized among experts in clinical trials, and are referred to in both the September 1993 FDA guidance and the ICH GCP document.

Objectives. Ultimately, the regulatory questions that FDA must answer in determining whether to clear a device to market are whether it is safe and effective (for devices undergoing PMA review), or substantially equivalent to a predicate product (for devices undergoing 510(k) review). However, neither of these questions is sufficiently specific to be used in developing a clinical protocol.

The first and key element of any study protocol must be a definition of the primary objective of the study or the essential research question to be tested. The study sponsor must state clearly the objectives of the study, and must formulate a specific hypothesis that will be tested to determine if the investigational device is safe and effective. FDA and the device sponsor should always agree on the study hypothesis before the first patient is enrolled. A flawed hypothesis will lead to a flawed clinical trial, from which the data will be insufficient to support a marketing application.

In deciding on the study objectives and hypothesis, several questions must be considered. Is the goal of the trial to show that the device performs better than or equivalently to the control? Is symptomatic relief sought or is a marked change in the disease process desired? Is the device to be used as the sole treatment regimen or will it be used as an adjunct to specified conventional therapy? The hypothesis will also invariably be tied to the types of patients to be studied.

In drafting the study hypothesis, the sponsor should always focus on the claims that will form the basis for marketing the device. For Class III devices, most marketing claims must have some foundation in the clinical study. Accordingly, the manufacturer should consider the study hypothesis and its design as part of its overall strategy for determining what marketing claims are necessary to have a commercially viable device.

Type of Trial. The study protocol should describe the specific type of trial to be conducted. Although clinical studies can be conducted at a single site, FDA strongly prefers that multicenter studies be used for devices that will require PMA submissions. Studies may be blinded or open, although blinding offers certain theoretical advantages. Study designs may be parallel, crossover, or factorial in nature--or variations on these themes.

Probably the most common design for device clinical trials is the parallel design, in which patients are assigned to one of two or more study groups, given the intervention for that group (that is, treatment with the device or with an appropriate control), and then followed to determine the outcome. A variation on the parallel design occurs in studies that are designed so that the patient acts as his or her own control. In such studies, baseline measurements are taken of the patient, the treatment or intervention is applied, the patient is followed, and the same measures are repeated. The before and after measurements are then compared, enabling patients to act as their own controls.

In a crossover design, each patient is given two or more treatments in a specified order. For example, some patients will receive treatment using the investigational device first followed by the control, and other patients will be treated using the control first. To avoid creating a carryover effect from the prior treatment, a washout period intervenes between study periods.

Factorial designs are also sometimes used in medical device clinical studies. In such trials, patients are assigned to one of two interventions (e.g., a new device or an active alternative therapy), to a control, or to both interventions. This type of study design is useful for assessing whether either intervention alone is effective, or whether a stronger or detrimental effect occurs when a combination of both treatments is received.

End Points. End points, or response variables, should be defined clearly and precisely. The sponsor should select a set of outcome variables that are as informative as possible, clinically relevant, and least prone to bias. Defining the specific end points in advance facilitates the tailoring of the study design and calculation of sample size. To ensure that there is agreement on the appropriateness of the sponsor's choices, important end points should be discussed with FDA prior to the initiation of the study.

End points can be either objective or subjective, depending on the device and the particular indications being studied, but they should be capable of unbiased assessment. Quantitative or categorical variables can form the basis for an end point. Thus, a change from one discrete state to another (e.g., living to dead), from one disease stage to another (e.g., from active disease to remission), or from one level of a continuous variable to another (e.g., level of pain) may underlie an end point. Sometimes response variables may be formed by combining a group of specified, individual measurements. Such a strategy can be useful when any one event would be likely to occur too infrequently to be observed in a reasonable number of patients, or when a combination of measurements is needed to comprehend whether the patient has truly improved clinically (e.g., a composite arthritis index that combines scores for stiffness; grip strength; and pain, tenderness, or swelling of the joints). The sponsor must also determine when during the course of the study the primary end point is to be measured.

The primary objective of the study must be addressed by primary end points, which form the principal bases for determining whether the device is safe and effective. To minimize confusion about the outcome of the trial, it is wise to limit the number of primary end points to one or two. A patient's outcome relative to a primary end point often results in the patient's response to treatment being defined as a success or failure, or in the patient being categorized as a responder or nonresponder. Understandably, the calculation of required sample size is based on an analysis of the primary end points. These should be distinguished from secondary end points, which are designed to address secondary study objectives.

For proving the safety or effectiveness of a device, FDA generally recommends against the use of surrogate end points--outcomes that are not themselves readily discernible as a clinical benefit to a patient but that may be correlated to a clinical benefit. For example, an improvement in some laboratory parameter may demonstrate that the device is working, but may not be widely understood as a clinical benefit to the patient. In some cases, however, FDA may find surrogate end points acceptable. A reduction in serum cholesterol, for example, may be an acceptable surrogate end point because its relationship to a clinical benefit is well described in the scientific literature. Where a surrogate end point is to be relied upon, it is essential that the study sponsor obtain a clear agreement with FDA that such an end point is appropriate.

Patient Population. The population of patients to be included in the clinical trial must be described in the study's eligibility criteria. These criteria will have a determinant effect on the ability of the sponsor to recruit patients as well as on the capacity of the study results to be generalized. It is therefore essential that sponsors develop clear, unambiguous inclusion and exclusion criteria when planning a clinical trial.

In practice, the patients actually enrolled in a study form a subset of the population defined by its eligibility criteria. Results of a study can only be generalized legitimately to patients similar to those enrolled in it. Thus, if the only patients enrolled in a study are those with mild or moderate disease, it may be difficult to apply its results to patients having a severe stage of the disease.

Inclusion and exclusion criteria typically relate to subject demographics such as age and sex, as well as to the stage of the disease being studied, pregnancy status, the patient's history with regard to certain chronic diseases, use of concomitant medications, the likelihood that the patient will complete all follow-up, and the presence of other confounding factors. FDA wants to ensure that investigators do not select patients based on personal preferences, thereby limiting the applicability of the device or masking some unidentified exclusion criteria. Study sponsors should therefore establish some mechanism to ensure that all eligible patients are offered an opportunity to participate in the study. To ensure comparability between the device and control groups, inclusion and exclusion criteria should be the same for all patients in the study.

The group of enrolled patients can be either homogeneous or heterogeneous in composition. A homogeneous study population may make the assessment of efficacy more straightforward, because it does not include prognostically distinct subgroups. However, if eligibility criteria are defined too narrowly, recruitment may be hampered and study results may not be readily generalizable. Heterogeneous populations may afford an opportunity to discover whether the device is effective in different subgroups of patients, but may necessitate a larger sample size to account for those subgroups. Determination of the acceptable level of heterogeneity for a study population is important for study sponsors.

Formulation of eligibility criteria should be guided by a sponsor's concern for patient safety and the need to demonstrate efficacy. Patients who will likely benefit from the device are obvious candidates. Subjects for whom the treatment is thought to be harmful or who are likely to withdraw from the study prematurely are often excluded. Marketing claims also should be considered in drafting eligibility criteria. If the company's marketing experts say that a specific patient population is essential for the ultimate commercial success of the device, that population must be represented in the study.

Investigational Device. The protocol should contain a characterization of the investigational device design, as well as a description of its principles and means of operation. The sponsors should pro-vide instructions regarding the manner in which the device should be operated, and should define the duration, frequency, and extent of its application.

Control Group. In recent years, ODE's unmistakable message to device manufacturers has been that some type of control is essential to the conduct of a device clinical trial. Having a control group permits the study sponsor to reason that the observed improvement in the treatment group at the end of the trial is due to differences between the investigational device and the control, and not to other factors.

Because there may be a wide range of biological variations among study subjects, and because different patients may respond differently to any given intervention, use of an uncontrolled clinical trial usually makes it impossible to ascertain whether a new device has made a difference in outcome. A controlled clinical trial enables sponsors to compare the effects of an investigational device in one group of patients to the effects of a control in another group of patients. Use of a control group permits the safety and effectiveness of an investigational device to be more clearly observed and subsequently evaluated in comparison to another therapy.

Several types of controls can be incorporated into clinical trials. Under certain limited circumstances studies can make use of self controls, patients for whom certain clinical variables are measured before and after implementation of the investigational device, and who therefore serve as their own controls. Active concurrent controls are patients under the direct care of the study investigator who are assigned to an intervention other than the investigational device (e.g., a placebo or alternative treatment); for comparative purposes, data about these patients are recorded on case report forms (CRFs). Passive concurrent controls may receive an alternative intervention, but are not under the direct care of the study investigator. Historical controls are a prior series of patients who should be comparable to the device group patients and who may or may not have received an active intervention; by definition, they are nonrandomized and nonconcurrent controls.

Historical controls are no longer in favor at ODE because it is difficult to establish that they are comparable to patients in the device group, and often the desired follow-up measures are not uniformly documented among them. Moreover, if an improved device is compared with historical controls using an older similar device, improvement in complication rates may derive solely from improved surgical techniques or improved concomitant therapy, rather than from a clinically superior device. Consequently, FDA's unmistakable preference is for clinical trials that make use of active concurrent controls. In the agency's view, use of concurrent controls makes it easier to evaluate comparability at baseline between the control and device groups and to ensure that both groups will be handled similarly during the course of the study.

Without doubt, it will be very difficult in the near future to rely on historical controls for device clearance. If a sponsor believes that use of such controls is justified, detailed discussions with FDA are essential, especially concerning the issue of matching the controls with the active patients. If the proposed control group is one described in the scientific literature, FDA and the sponsor must agree on whether that literature provides sufficient detail about the control patients to provide an adequate basis for comparison.

Selecting controls for device studies is more problematic than for drug studies. Devices or medications selected as controls should have been previously approved by FDA. Examples of controls that can be used in clinical trials of medical devices include older versions of the same device, different devices, sham devices (devices that look the same as the test device, but do not deliver therapy), medications for the same intended use, other surgical procedures, and no therapy (that is, the natural history of the medical problem if left untreated). When selecting a control, manufacturers should bear in mind that it is often easier to obtain market approval from FDA when the new device performs better than an alternative therapy than when its performance is merely equivalent to the control.

Assignment of Intervention. At baseline--before treatment with the investigational device or the control begins--the control and device groups should be similar, so that differences in outcome may be reasonably attributed to the device being studied. Otherwise, it is often difficult to meaningfully compare the rates of therapeutic success in the two groups, even with statistical adjustment. Accordingly, it is essential that relevant factors be assessed at baseline to determine whether the treatment and control groups are comparable, and whether statistical adjustment is feasible if they are imbalanced.

Assignment of patients to the investigational device group and the control group in a systematic manner that avoids selection bias is an important aspect of sound study design. Selection bias occurs when patients with certain characteristics are more readily assigned--intentionally or unintentionally--to one treatment group than to another. The result of selection bias is that patients who are characterized by important prognostic factors may be disproportionately assigned to one group, thus confounding the interpretation of any differences in outcome between the groups.

It is generally accepted that randomization is the preferred method of assigning patients to study groups in order to minimize selection bias. Randomization tends to guard against imbalances between groups, protects against conscious or unconscious actions of study investigators that could lead to biased assignment of patients, and provides the probabilistic basis for most statistical analyses. Randomization can be carried out centrally by the sponsor, or locally by each study investigator.

Depending on the study, randomization procedures can be tailored to specific needs. For example, in block randomization an equal number of patients are assigned to the various treatment groups from a specified number of enrollees (e.g., randomizing three patients to the device group and three patients to the control group for every block of six patients). In most medical device clinical trials patients are assigned in equal numbers to the device and control groups, but this is not always necessary. If it is practically difficult to recruit an equal number of control patients or if there is a considerable body of knowledge describing how the control group is likely to behave, then a higher ratio of device patients may be appropriate.

Sample Size. In its 1993 report, the Temple committee observed that clinical trials in which sample size requirements were not carefully considered lacked statistical power or the critical ability to detect device effects of clinical importance.1 Because the number of patients to be recruited is significant to all phases of the clinical study, this issue must be considered early in the planning stage.

FDA frequently requires that sponsors provide a complete statistical justification for their proposed sample size. Sample sizes for studies of therapeutic devices typically vary from less than 100 to nearly 300 patients; for studies of diagnostic devices several hundred to more than 1000 samples may be needed.

Intuitively, the greater the anticipated clinically meaningful differences between patients treated with a new device and those treated with a control, the smaller will be the number of patients required to demonstrate those differences. Similarly, the smaller the anticipated differences, the larger will be the number of patients required to detect whether there is a real difference. When a company is designing a study to show that its device is equally effective as another, however, intuition may not be a sufficient guide for selecting an adequate sample size.

The sample size required for a clinical study is determined by testing it against the particular hypothesis stated by the sponsor. For example, the null hypothesis may be that the proportion of patients with a successful outcome in the investigational device group is the same as that in the control group. In testing this hypothesis through the clinical study, two types of error can be made. A Type I error occurs when the null hypothesis is incorrectly rejected--that is, when it is concluded that the test device is better, when in reality it is no better than the control. A Type II error occurs when the null hypothesis is incorrectly accepted--that is, when it is concluded that there is no difference even though the test device is better. The probability of this error is referred to as beta (ß), and 1 ­ ß is the power of the test or the ability to detect a real difference of a specified magnitude between treatments. ODE usually prefers to see hypotheses tested at a 5% level of significance with at least 80% power.

Factors that affect determination of sample size include the primary end point to be analyzed, the selected size of Type I and II errors, and assumptions about the anticipated success rates in the device and control groups. When planned or anticipated, subgroup analyses, significant variations between study centers, prerandomization stratification, and study dropouts may also affect the proposed sample size. Whether a study is designed to show a difference in effectiveness or equivalence to a predicate device will also have an impact on sample size calculations.

Masking. If patients are aware they are receiving a certain treatment, they may imagine they are experiencing certain beneficial or adverse effects. If investigators know the intervention assigned, some subjects may not be followed as closely as others, or some adjunctive therapies may be disproportionately applied to one group of patients. To reduce the potential for bias arising from these sources, clinical trials often make use of masking, also called blinding.

Masking can take various forms in clinical trials. In an unblinded study, both the patient and study investigator know what treatment has been assigned. In a typical single-blind study, the investigator knows what treatment has been assigned, but the patient does not. In a double-blind study, neither the investigator nor the patient knows the assignment of intervention. Sometimes modified double-blind studies are conducted, where the study investigator responsible for implementing the device knows the treatment assignment, but the observer responsible for evaluating safety and effectiveness outcomes is unaware of the treatment assignment. Triple-blind studies include those where, in addition to the patient and investigator being blinded, the committee monitoring or analyzing the study results does not know the identity of the groups.

Objectives.

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INTERNATIONAL CONFERENCE
ON HARMONIZATION PRINCIPLES
OF GOOD CLINICAL PRACTICE

1. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP [good clinical practice] and the applicable regulatory requirement(s).

2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

3. The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

4. The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

6. A trial should be conducted in compliance with the protocol and amendment(s) that have received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.

7. The medical care given to, and medical decisions made for, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

8. Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

9. Freely given informed consent should be obtained from every subject prior to clinical trial participation.

10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

12. Investigational products should be manufactured, handled, and stored in accordance with the approved protocol and amendment(s).

13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.


ESSENTIAL ELEMENTS OF A
CLINICAL TRIAL PROTOCOL

Clearly specify the objectives of the study, including primary and secondary objectives.

Type of Trial. Describe the type of design of the clinical trial (e.g., single or multicenter, type of blinding, parallel or crossover).

End Points. Describe the primary and secondary end points.

Patient Population. Describe the population to be studied, enumerating all inclusion and exclusion criteria.

Investigational Device. Describe the device to be studied and how the treatment will be administered with the device.

Control Group. Describe the nature of the control to be used in the study (e.g., randomized, concurrent, control; historical control; or patient as own control).

Assignment of Intervention. State how patients will be assigned to each study group (e.g., via randomization).

Sample Size. State the number of subjects planned to be enrolled and provide a statistical justification for the proposed sample size.

Masking. Discuss masking or blinding of patients and health-care providers.

Study Procedures. Enumerate all procedures, examinations, and other evaluations to be conducted at each visit.

Study Assessments. Specify safety and efficacy parameters, including the methods and timing of such assessments.

Study Duration. State the projected length of recruitment and patient follow-up periods.

Adverse Device Effects. Enumerate the nature and frequency of all anticipated adverse device effects.

Data Analysis Plan. Prospectively formulate a data analysis plan, including a description of the statistical methods to be used and the timing of any interim analyses.

Study Monitoring. Describe the procedures for monitoring patient and investigator compliance.

ELECTRONICS : Comparing Insulating Materials for Electrosurgical Instruments

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published February 1996

Peter Kleinhenz and Christine Vogdes

Used in conjunction with an electrosurgical unit (ESU) that supplies the necessary power, electrosurgical devices are a routine part of both laparoscopic and open surgical procedures. These devices can cut, cauterize, and coagulate tissue by means of radio- frequency (RF) electrical energy. Typically, some form of insulation is needed to ensure that energy is directed at the target tissue. Heat-shrink tubing is a preferred method of providing such insulation on electrosurgical tools, particularly on high-volume disposable products such as graspers, scissors, hooks, and probes. Unfortunately, defects in the insulation can allow the full amount of RF energy to be applied in unintended and unseen areas, causing burns or cuts that may not be detected at the time of surgery.

The potential for the unintended and unseen application of RF energy is especially great in laparoscopic surgeries because the surgeon's field of view is restricted to the viewing angle of the laparoscope. Most laparoscopic instruments are approximately 35 cm long and the images viewed on the monitor show less than 5 cm of the distal end of the device. Although the electrode used to deliver RF energy has an insulated covering, 90% or more of this insulation is outside the user's viewing range.1 It has been reported that the incidence of recognized injuries for laparoscopic surgeries is between one and two patients per 1000 operations.2 In addition, several medical journals have indicated that the majority of such injuries go unrecognized at the time of surgery, either because the affected site was not observed during the procedure or because there was no immediate clinical evidence of the in- jury--the time from injury to onset of symp-toms can vary from 18 hours to 14 days.3­5

When injuries go unnoticed during surgery, the reasons for their occurrence can only be inferred. The most common explanations include: inadvertent grasping or touching of tissue while the device is energized, direct coupling of the device to surrounding tissue while the device is energized, and insulation failures or defects.6 One clinical study has concluded that the greatest contribution to accidental injury is probably inappropriate or inadequate insulation.2

The potential for insulation-related injury can be minimized by selecting insulating materials based on the results of standard tests. With the goal of improving insulation quality, the authors' companies worked together to create a test apparatus and a test protocol to evaluate various shrink tubing materials used by the electrosurgical product industry. The results of that collaboration are reported below.

THE HF18 STANDARD FOR ELECTROSURGICAL INSTRUMENTS

The Association for the Advancement of Medical Instrumentation (AAMI) has established minimum safety and performance requirements for electrosurgical devices, which were adopted by the American National Standards Institute (ANSI) and are detailed in the document designated ANSI/AAMI HF18-1993.7 Because the collaborative project began in 1993, prior to the latest revision of this standard, and concluded in early 1995, the experimental test methodology and protocol was based on both HF18-1993 and HF18-1986.8

In paragraph 4.2.5.4 (6), the HF18-1986 standard requires that insulated shafts pass a 30-second test at 4000 V peak to peak at 1 MHz. This combination of high voltage and high frequency represents a very severe challenge and therefore provides a high margin of safety. A typical ESU operates in the 3000-V range at 500 kHz. One of the difficulties in applying HF18-1986 has been that there was no standard test equipment that operates in the suggested 4000-V, 1-MHz range. Consequently, there has been some confusion on the part of instrument manufacturers on how to comply with this requirement. It was in order to resolve some of this confusion that Raychem, a supplier of insulating shrink tubing, decided to undertake a benchmark study of various competitive materials and their ability to comply with HF18-1986. Progenics, an experienced designer of ESU devices, was selected to build the test apparatus and generator. In Phase I of the study the key questions addressed were: (1) Which of the commonly used insulating materials meets the AAMI standard? (2) What is the effect of varying the wall thickness of an insulating material? and (3) What is the effect of having air rather than normal saline surrounding the material during testing?

Based on the results of Phase I, a second-phase test plan was developed to study the effects of multiple energizing cycles, gamma and ethylene oxide (EtO) sterilization, installation errors, and stresses created by a step transition. Compared with the first-phase efforts, this expanded test plan more closely paralleled the potential stresses that insulating materials encounter during instrument manufacture and use. While the test program was under way, the 1993 revisions to HF18 were issued. Paragraph 5.2.5.4 changed the output-voltage test requirement to 1.5 times the output voltage at the specified operating frequency of the ESU. Therefore, Progenics selected 6000 V peak to peak as the new voltage setting of the test apparatus because that is 1.5 times the 4000 V recommended for the test generator. A 500-kHz frequency was selected as representative of the average operating frequency for an ESU.

TEST METHODS AND RESULTS

The test generator and apparatus were designed to meet the test specifications in the 1986 HF18 standard, which called for laying an insulated mandrel on a ground plane and testing the sample in air or with a saline-soaked sponge covering it. The associated test equipment includes power supplies, a 1-MHz amplifier with a 4000-V output transformer, and an oscilloscope to measure current and voltage (see Figure 1).

During both phases of testing, the shrink tubing was installed on steel mandrels with a heat gun to remove entrapped air and then finished with a 3-minute oven soak. In Phase I tests, single and multiple layers of material were installed to test the effect of varying the material thickness. Because HF18 requires high-voltage testing, the samples were slowly powered to the peak voltage and then held at that voltage for the required 30 seconds. For all test runs, observations were recorded on the presence and location of a luminous discharge (corona) at the surface of the insulating material and the electrical conductor. The voltage at breakdown and the time to failure were also recorded.

Phase I. The Phase I tests evaluated six different insulating materials from various manufacturers: polyvinylidene fluoride (PVDF), low-density polyethylene (LDPE), a blend of polyolefin and ethylene acrylic acid copolymer that is partially zinc or sodium neutralized (ionomer), high-density polyethylene (HDPE), two types of fluorinated ethylene propylene (FEP), and polyvinyl chloride (PVC). For each material, 12 or 15 samples (3 each of 4 or 5 thicknesses between 0.008 and 0.016 in.) were tested at 4000 V peak to peak, 1 MHz in both air and normal saline.

The results of those initial tests are shown in Table I. The data indicate that the PVC and PVDF materials did not pass the 4000-V, 1-MHz test even at 0.016 in., the largest thickness tested, and the other materials required a thickness of 0.015 in. or greater to pass. There was no significant difference in the results when air and saline were used as the media surrounding the test materials. If a material passed the test in air, it was also a good insulator in normal saline. This capability is important because electrosurgical instruments come in contact with such saline formulations as blood and human tissue and certain bipolar instruments are used specifically in conjunction with saline washes.

The test results were found to be consistent with the known dielectric properties of the individual materials. In addition, they were consistent from sample to sample within a group, which indicated the materials were uniform in quality. The fact that the test data suggest that candidate insulators should be at least 0.015 in. thick raised a significant question, because many electrosurgical instrument manufacturers currently use insulation 0.008 in. thick without adverse effects.

Phase II. Based on the success of the initial test model, a more rigorous testing matrix was developed for a Phase II program, which explored the effects of repeated energizing, stress flaws, poor installation techniques, and sterilization on insulating ma-terials. Stress flaws in the insulation were simulated by press-fitting rings of copper tubing on the steel test mandrels to create an area of sharp transition. To simulate poor installation techniques, samples with visible air bubbles or poor contact with the mandrel were created through underheating. In general, the goal of this phase was to understand why many commercially available surgical instruments perform acceptably even though they have thinner insulation than the results of the first round of testing would suggest were required for safety.

The Phase II study only evaluated samples of three materials that had performed well in the Phase I tests: LDPE, the ionomer blend, and FEP. Unless otherwise noted, all of the tests used the 4000-V, 1-MHz test apparatus for a 30-second duration. The first series of tests involved testing the materials before and after they underwent EtO or gamma sterilization cycles, and it was determined that there was no significant decrease in the performance of any samples based on these sterilization conditions. Next, the samples created with deliberate defects such as air bubbles, pockets, and wrinkles were evaluated, and, for all three materials, samples with a wall thickness of 0.015 in. or greater passed. The performance of thicker samples was not evaluated because experience indicated that they would pass the test.

The test results for the third set of samples, which used a stepped mandrel to simulate sharp transition­type stresses, were not conclusive. Stepped mandrel samples that were 0.011 in. thick performed approximately the same as nonstepped samples with a similar thickness. The fourth area for investigation was the effect of repeatedly energizing the same area of a sample; even after each sample mandrel had undergone 10 test cycles there was no deterioration in the performance of the insulating materials. The results of these Phase II tests simulating manufacturing and use conditions are summarized in Table II.

After the 1993 revision of HF18 was issued, it was decided to retest some of the thinner-wall samples that had marginal-to-poor performance during the first series of tests. The materials that were reevaluated were LDPE, the ionomer blend, HDPE, and FEP. Tests were performed at 6000 V peak to peak and 500 kHz to satisfy the new requirements of HF18-1993, and all of these materials passed, even at wall thicknesses of 0.008 in. The materials passed at the lower frequency and higher voltage because reducing the frequency increased the capacitive reactance of the materials. When the frequency decreases, the potential for leakage current decreases, thereby reducing the chance for the insulating materials to break down. Table III compares the results of tests at 500 kHz with the original results at 1 MHz.

CONCLUSION

The creation of appropriate test equipment and a test protocol made it possible to quickly screen typical insulating materials to the specifications of HF18-1986. Results were consistent for samples of the same material and correlated well with the predicted material performance. The test equipment and protocol also permitted the researchers to study areas of particular concern, such as the effects of improper installation and sterilization degradation of insulating materials. Finally, retesting the materials to the different electrical conditions specified in HF18-1993 led to an understanding of the discrepancy between previous test results and the actual performance of instruments currently in use. Several conclusions were drawn from these efforts, including the following:

* HF18-1986 specifies a very severe test for insulating materials used in electrosurgical devices. Only materials such as FEP, LDPE, HDPE, and the ionomer blend that are >= 0.015 in. thick can pass this test unconditionally. By separating these better high-frequency insulating materials from poorer insulators such as PVC and PVDF, the HF18-1986 test provides a high margin of safety.

* There is no significant difference in electrical performance between FEP and polyolefins such as LDPE, HDPE, and the ionomer blend. This comparability is important to instrument manufacturers because polyolefins are easier to install, less costly, and more able to withstand radiation sterilization than FEP is.

* The medium used to surround the insulating materials during testing has no significant effect on their performance. Results were the same for tests at 4000 V, 1 MHz in both air and saline. Various sterilization methods and poor installation practices did not significantly influence the materials' insulating capabilities either, nor did cycling up to 10 times at 4000 V, 1 MHz.

* Reducing the test frequency from 1 MHz to 500 kHz had a very strong effect on the results. FEP and polyolefins such as LDPE, HDPE, and the ionomer blend with wall thicknesses down to 0.008 in. were capable of withstanding 6000 V peak to peak for 30 seconds at 500 kHz. This capability correlates well with the known instrument-manufacturing practice of using insulating materials between 0.005 and 0.015 in. thick.

* The test specifications in HF18-1993 more closely parallel instrument insulation requirements in actual use than did those in HF18-1986. However, engineers might consider using a higher-frequency test like the HF18-1986 standard to screen candidate materials during the design phase of electrosurgical instrument development.

REFERENCES

1. Odell RC, "Laparoscopic Electrosurgery," in Minimally Invasive Surgery, Hunter JG (ed), New York, McGraw-Hill, pp 33­41, 1993.

2. Nduka CC, Super PA, Monson JR, et al., "Cause and Prevention of Electrosurgical Injuries in Laparoscopy," J Am Coll Surg, 179: 161­170, 1994.

3. Strasberg SM, Sanabria JR, and Clavien PA, "Complications of Laparoscopic Cholecystectomy," Canadian J Surg, 275­280, 1992.

4. Leahy AL, Bouchier-Hayes DB, and Hyland JM, "Early Experiences of Laparoscopic Cholecystectomy in Five Irish Hospitals," Irish J Med Sci, 161:410­413, 1992.

5. Voyles CR, and Tucker RD, "Education and Engineering Solutions for Potential Problems with Laparoscopic Monopolar Electrosurgery," Am J Surg, 164(1):57­62, 1992.

6. Voyles CR, and Tucker RD, Essentials of Monopolar Electrosurgery for Laparoscopy, Electrosurgical Concepts, 1992.

7. Electrosurgical Devices, ANSI/AAMI HF18-1993, Arlington, VA, Association for the Advancement of Medical Instrumentation (AAMI), 1993.

8. Electrosurgical Devices, ANSI/AAMI HF18-1986, Arlington, VA, AAMI, 1986.

Peter Kleinhenz is president and CEO of Progenics Corp. (Columbus, OH). Christine Vogdes is principal scientist at Raychem Corp. (Menlo Park, CA).

ENVIRONMENTAL CONTROL : Building the Right Cleanroom Environment

Medical Device & Diagnostic Industry Magazine | MDDI Article Index

Originally published February 1996

Robert J. Pellizzi

Production managers in the medical device industry have long faced the need to determine the appropriate production environment for a given product. It is essential to decide whether a product or process calls for a clean manufacturing environment in which airborne particulates, temperature, humidity, airflow patterns, and other factors are controlled. Beyond that, production managers must also determine whether a clean workstation is sufficient or whether a cleanroom should be constructed.

In making the determination, questions to consider include: Does a cleanroom provide additional benefits that would justify the cost of building and maintaining one? What are the regulations surrounding cleanroom environments? What products or processes dictate the need for such an environment? This article reviews U.S. and foreign regulations and standards that address the need for a cleanroom or controlled environment. Although FDA's good manufacturing practices (GMP) regulation, International Organization for Standardization (ISO) 9000 quality systems standards, and European Norms (EN) documents provide guidelines for building and maintaining cleanrooms, none states what products or processes require such an environment.

DEFINING CLEANROOM

A cleanroom is designed to enable manufacturers to control particulate contamination, temperature, and, where necessary, humidity. It controls the introduction, generation, and retention of particles in the room, protecting the product or process from air- or humanborne contaminants. The main difference between cleanrooms and controlled environments is that cleanrooms must be certified by an independent agency such as the Institute of Environmental Sciences. When discussing cleanrooms, controlled means to develop a specification for a specific parameter, such as air quality, temperature, or humidity; monitored means to track the controlled parameter on a regular basis; and certification is a procedure to verify that the process is under control.

CONTROLLED ENVIRONMENTS

By contrast, a controlled environment is a specified working area that primarily controls one or more physical, chemical, or biological variables. Although a controlled environment is similar to a cleanroom in that it is controlled and monitored, a controlled environment is not certified. Moreover, it is not subject to federal cleanroom requirements for construction and operation.1 For example, one Florida device manufacturer uses a Class M6.5 (100,000) clean area. Technically, it is only a controlled environment because it does not meet airflow requirements established in Federal Standard (FS) 209E. It is, however, regularly monitored for particle concentration, and FS 209E requires that this information be available for FDA inspections or audits.

Once the need for a clean environment has been determined, the cleanliness level must be considered. Both cleanrooms and controlled environments require regular maintenance and cleaning. Each requires limits that dictate appropriate corrective action when the controlled parameter fails to meet established limits.2,3

REGULATORY REQUIREMENTS

The regulations do not indicate what environmental, product, or facility parameters to control. The regulations provide only the standards a company must meet after it decides to manufacture the product in such an environment. Using a controlled environment rather than a cleanroom often equates to significant cost savings during initial construction and in planned, periodic maintenance. The primary reason for building a cleanroom is to account for future economic considerations.4

Several regulations apply to production environments, and many sources provide guidelines for meeting standards set forth in the regulations.5­7 Section 820 of the Code of Federal Regulations addresses the requirements for medical devices; section 211 addresses pharmaceutical products; and FDA has published guidance based on FS 209E. ISO standards provide specifications to achieve a CE marking, and BS (British standard) 5295 provides standards for that nation. The EN documentation is a voluntary standard in use in Europe. GMPs and other regulations simply describe a set of criteria to which all products and processes--not the cleanroom itself--must adhere. The regulations require that the systems be in control. The methods needed to achieve control are not stated.

ISO standards and GMP regulations provide guidance for setting the parameters for controlling processes. This type of control enables companies to produce consistently good-quality products. The majority of the changes in the revised GMP affect design considerations. Another significant modification affecting cleanrooms is the change in language to coincide with the ISO 9000­ series standards.

Although many regulations and standards provide guidelines for design and construction of controlled environments, none--GMPs, ISO 9000, or EN documents-- mandates cleanrooms for certain types of products. GMPs and ISO documents require that all processes be in control, and that certain product types be manufactured in a controlled environment. FDA does not determine whether a company should manufacture a given product in a cleanroom or controlled environment. However, for a company seeking a premarket approval, the approval process is easier if the product is manufactured in a cleanroom. If a company does not use a cleanroom, FDA requires that it validate the manufacturing processes and environment.

If all companies producing a similar product did so in a Class 10,000 cleanroom, then a competitor applying for approval would also likely need to have a cleanroom. Practices by other manufacturers often set the standards for environmental and process specifications. FDA recommends that if a cleanroom is not part of a company's plans, the company should provide documentation, including protocols, that validate the facility and processes.

HOW THE REGULATIONS FIT IN

The GMP sections 820.40 (building) and 820.46 (environmental conditions) state, in part: "Buildings in which manufacturing, assembling, packaging, packing, holding, testing, or labeling operations are conducted shall be of suitable design and contain sufficient space to facilitate adequate cleaning, maintenance, and other necessary operations." In the revised GMP, these sections have been deleted and the subjects are now addressed in section 820.70 (production and process controls):

(c) Environmental control. Each manufacturer shall establish and maintain requirements for the environment to which product is exposed. Where environmental conditions could have an adverse effect on a device's fitness for use, these environmental conditions shall be controlled, and procedures for such controls shall be established and maintained. Any environmental control system shall be periodically inspected to verify that the system is adequate and functions properly. Results of such inspections shall be documented and reviewed.

(f) Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups, and assure orderly handling.

FOREIGN GUIDELINES

Section 3.1.1 of the British standard, BS 5295, states: "Ideally, buildings should be purpose-designed and built but whether newly constructed or modified, the following are basic considerations: part or all of the production shall take place in a controlled area or cleanroom. . ."

Section 4.9.1 of ISO 9001 (process control, general) states: [Manufacturers] shall identify and plan the production, and where applicable, installation processes which directly affect quality and ensure that these processes are carried out under controlled conditions." It also states, "controlled conditions shall include the following: documented work instructions and monitoring and control of suitable process and product."

THE BOTTOM LINE

The final decision for manufacturing in a cleanroom or controlled area is determined by ensuring that processes meet the specifications set forth in written procedures, with audits in place to provide a safe, efficacious product. The type of manufacturing area chosen should not only meet this basic requirement, but also take into account future use of the area and efficient use of available funds.

Much is written about cleanrooms: how to design, build, upgrade, clean, fix, and monitor them. There is very little, however, written on the circumstances that mandate a cleanroom or controlled environment. Some simple steps can make the decision-making process easier.

* Determine the product characteristics and end use, the processes, and the equipment necessary to produce the product. Carefully consider the product and the adverse effects various environmental conditions would have on it. This is particularly important when manufacturing integrated circuits. Consider the effect of humidity. Does the product contain metals that are affected by moisture? Will temperatures affect the hardness of plastic or rubber parts? Will humanborne contaminants adversely affect the process? Does the equipment need special venting, or does it generate a large amount of contamination?

* Decide which type of facility will meet the environmental requirements for the product, process, and equipment. It is important to analyze alternatives to having a cleanroom. For example, for a small packaging operation, a clean workstation or a clean work zone within the manufacturing area may be sufficient. It is also possible to isolate a particular piece of equipment to minimize noise level or contamination. These environments enable the company to establish a level of contamination control without having to construct a cleanroom. For each process parameter there must be a written specification, action limits, and a corrective action plan in place for when limits are exceeded.

* Provide necessary documentation. Formal documentation must detail training programs, processes, and the specifications for the product. Evaluate the regulations carefully.

A decision to build a cleanroom or to control a production environment is often affirmed in situations such as the following:

* The accounting department allocates enough funds to construct a Class 100,000 cleanroom. The company then must upgrade as more money becomes available.

* The engineering department indicates that a cleanroom or controlled environment would reduce the number of rejected products.

* The product's primary competition is produced in a cleanroom.

* Technical publications and industry trade shows indicate a new trend toward a particular class of cleanroom, or control of a specific parameter for some type of process.

* A prospective or long-time customer requests products built in a cleanroom or controlled environment.

* The marketing department can more readily tap a larger market if the company can demonstrate a high-tech image using state-of-the-art automated equipment.

* Having a cleanroom provides leverage for bidding on new jobs.

A recent trend indicates a general shift in the medical device industry away from cleanrooms. Construction costs for a cleanroom facility, along with its maintenance and certification, are extremely high. Average construction costs for a cleanroom range from approximately $260/sq ft for Class 100,000 to about $525/sq ft for Class 100. In addition to this sizable initial investment, normal maintenance costs are about $75/sq ft.

Pat Law of HepaTest, a cleanroom builder and certifier in Longwood, FL, recommends a program of tight limits of environmental parameters, a plan that includes action limits and corrective action when these limits are exceeded, and a monitoring program that includes complete documentation as an acceptable alternative to a cleanroom. Regardless of whether a company uses a controlled environment or cleanroom, self-audits and FDA audits must include data collected periodically to ensure parameters are under control.

THE FINAL STEPS

If eliminating airborne particulate contamination is crucial to a process or product, then a cleanroom is probably the best choice. A Class M5.5 (10,000) satisfies FDA requirements in most situations. This level provides a good background area when critical operations are set to cleaner standards by clean zones (laminar-flow workstations, for example).

When clean air is desirable but not crucial to the product, a cleanroom is unnecessary as long as formal specifications are stated as part of an investigational device exemption, 510(k), or other product application. Monitoring of all environmental parameters necessary to the process is required regardless of whether the product is manufactured in a cleanroom or in a controlled environment. Scientific testing and validation of a product and the processes necessary to produce it may preclude the expense of building and maintaining a cleanroom or controlled environment.

CHOOSING A DIRECTION

Several factors help determine the need for a particular type of facility: type of product, process, and equipment used to produce it, and supporting concepts such as potential business, image, or financial concerns. Emotion will play a part in the decision-making process. An industry rule of thumb states, "Cleanrooms should be two orders of magnitude cleaner than we really need."

The latest revision of the GMP differentiates devices for their design quality considerations. It also includes requirements for Class I devices. Such devices should be manufactured in a Class M6.5 (100,000) or better cleanroom. Packaging operations should take place in a much cleaner zone, preferably a Class 100.

Manufacturers interested in controlling a manufacturing environment or building a cleanroom should investigate the nature of the control or contamination process and its relationship to product yield. Although no formal declaration determines a manufacturing environment, manufacturers should evaluate the possible need for a controlled environment for all Class II and Class III devices.

REFERENCES

1. Schneider RK, Gerbig FT, Lemons R, et al., "What Class of Cleanroom Do You Really Need?" in Proceedings of Cleanrooms '91, Flemington, NJ, Witter Publishing, pp 101­105, 1991.

2. Pellizzi RJ, "Cleanrooms and Controlled Environments: What is Needed? What is Recommended?" in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C1-1­C1-4, 1994.

3. Hansz TE, and Linamen DR, "Planning, Design, and Construction of a New Cleanroom Facility," in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C2-1­C2-32, 1994.

4. Matthews RA, "The Cleanroom Edge: Does Your Company Need It?," in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C2-1­C2-32, 1995.

5. Code of Federal Regulations, 21 CFR 820.

6. "Working Draft of the Current Good Manufacturing Practice (CGMP) Final Rule," Docket 9ON-0172, Rockville, MD, FDA, Center for Devices and Radiological Health, 1995.

7. Quality Systems--Model for Quality Assurance in Production and Installation, ISO 9002, Geneva, Switzerland, International Organization for Standardization, 1987.

Robert J. Pellizzi is general foreman for Cordis Corp. (Miami Lakes, FL).