Sterilization technology is basic to preparation of pharmaceuticals and vaccines, the manufacturing of medical devices and hygiene products, food processing and many other fields. Many products sold for HealthCare applications are labeled "sterile". This terminology is conventional in the medical trades but is misleading. Industrial sterilization does not lead to 'absolutely' sterile products. Instead, it produces objects where the population of surviving micro-organisms is less than at the starting point. Different sterilization processes lead to different surviving population levels of micro-organisms.

Bandages and surgical products intended only for brief contact with tissue and body fluids are in the least demanding category. It is an established practice to submit them only to the lowest level of sterilization. Therefore, such products contain appreciable levels of surviving viable entities. More sophisticated medical products and instruments for critical applications may undergo rigorous sterilization processes which ensure much lower populations of possible surviving micro-organisms. For practical purposes, industrial sterilization never leads to 'absolutely' sterile products without probability of surviving micro-organisms.

Clinical Basis for Performing Sterilization:

Living systems are often dependent on symbiotic processes. Thus, living systems may coexist with specialized populations of micro-organisms which perform beneficial or even essential functions as part of the system. Mammalians and many other species depend on microbiologically driven phenomena to achieve certain essential functions such as digestion and metabolization of certain waste products. The health of a living system in coexistence with viable microorganisms is not a universally accepted concept.

Since the late-1800s, it has been acknowledged that micro-organisms can be pathogenic and that medical procedures ought to be guided by rules of cleanliness supplemented by efforts to minimize the introduction of microbiological matter incidental to medical treatment. Protocols which surround medical procedures have subsequently placed major importance on ensuring minimal populations of micro-organisms on HealthCare products and instruments. Yet it is also acknowledged that micro-organisms can safely coexist in certain parts of living organisms. Thus, a duality in thinking has emerged with the result that certain classes of micro-organisms constitute clear and present risks of adverse effects whereas others do not.

Terminology which emerged in the twenties and thirties reflects this duality. The term 'infection' became associated with a rapid and threatening manifestation from foreign microbiological entities whereas 'colonization' was deemed to be proliferation of organisms at a site which may or may not have been thought as immediately threatening. During the following period, technologies for the control of pathogens evolved and additional terms emerged to define undesirable situations involving micro-organisms

The term "nosocomial" was introduced to define threatening entities associated primarily with HealthCare procedures and institutions but these included narrow classes of bacteria and related flora. Later, certain micro-organisms found habitually in tissue and organs and originally thought benign, emerged as highly pathogenic. Illustrative examples include bacterial entities responsible for upper digestive tract ulcers, benign skin flora as undesirable fibrotic vectors in wound repair and entities that promoted adhesions following surgery. Bacteremic manifestations from ingress of intestinal flora in blood was discovered early but detailed studies on mechanisms did not appear until World War II. In the practical sense, there was an intuitive fear of any micro-organisms released within some inner compartments of living systems but others were deemed more resistant to such contaminants. Translated in a clinical context, it became traditional to minimize the introduction of viable organisms incidental to HealthCare procedures, in particular for surgery but not all compartments were treated in the same way. This view was derived largely from a general belief that antibiotics can overwhelm inimical micro-organisms and pathogens if clinical complications emerge.

For these reasons, it became traditional to sterilize HealthCare products hoping for the minimum number of surviving entities. However, economic and manpower considerations imposed limitations on the thoroughness of the process and thus scales of need for sterility levels emerged. Depending on the applications, the degree of stringency of sterility-inducing processes was allowed to vary from nearly exhaustive hoping for absolute sterility such as in neurological applications to much more lax requirements that tolerated significant amounts of microbiological survivors in products intended for abdominal surgery involving the lower digestive tract.

Sterilization Efficacy and Techniques:

There are many techniques that can be employed to perform sterilization. They vary in cost and labor. Not all are equivalent or suitable for applications involving medical supplies. Some are specifically designed for very narrow applications. Except for specialists directly involved with industrial or institutional sterilization, these processes are not widely understood even within professional circles versed in microbiology. Contrary to frequently expressed views, the terms "sterilized" and "subjected to sterilization" as applied to an item or a product, do not imply a sterile object. All sterilization processes lead to reduction in the quantity, activity and virulence of micro-organisms but few of these processes lead to total destruction of the targeted entities. Instead, they result in items that have a lesser probability of harboring viable microorganisms depending on the lethality of the process.

Absolute sterilization is theoretically possible using extremely reactive chemicals or heat. In rare instances, processes that employ very elevated temperatures can carbonize all organic material to produce 'absolutely' sterile products devoid of any organic matter. Such processes are not commonly employed for medical products as they would severely damage or destroy most products including cellulosics, plastics and even some alloys that are unable to sustain high temperature. Conversely, some simple metallic, glass and ceramic objects can sustain such processes and sterilization based on carbonization technologies may be employed in this context, as is occasionally done for aerospace and electronic applications.

Sterilization and Decontamination - Related but Separate Issues:

Very few HealthCare-related sterilization processes actually remove micro-organisms and preexisting contaminants. Additional steps may be required prior to final sterilization in order to achieve the required degree of sterility. Non-viable contaminants must also be removed with other techniques in order to improve the reliability of some processes. All industrial and institutional sterilization processes leave variable amounts of biologically active substances derived from the killed organisms. Residuals of the sterilizing agents may also remain thus increasing the level of non-viable contamination.

It is conventional to perform validation studies on sterilization processes as applied to a given product. Sterilization techniques must be adapted to the product, the way in which it is packaged, the end-use that will be made of it, the number and the way in which the item is grouped together with similar objects. The geometry of the sterilization system and other physico-chemical factors intrinsic to the equipment used will affect efficacy. To this end, elaborate techniques using sterility indicators with calibrated bioburdens of referenced microorganisms will be interspersed within a sterilization load and assayed for surviving entities. Assay techniques must confirm the destruction of unwanted micro-organisms to the level required for all items in the sterilization load and must measure the "lethality" of the process as referenced to the sterilized object.

By-products of sterilants with contaminants and biological debris such as killed microorganisms are also formed incidental to sterilization. These residuals may present non-infective risks, in particular, if they are proteins and toxins from bacteria and fungi. Items with large amounts of proteinaceous contaminants of this kind are termed "pyrogenic" and may present significant risk of adverse reaction. Sterilization efficacy and usefulness of a given process depend on the type and amount of viable entities and the level of non-viable contaminants that are initially present on the object as well as the way in which these entities are distributed on the object. Thus, a given sterilization process does not always lead to a product with superior clinical safety or efficacy.

Impact of Sterilization Processes and Packaging on Sterilized Products::

Sterilization methods can impact on properties of the product and its packaging. Many clinically useful products are sensitive to harsh treatments of any kind and treatments that could destroy viable organisms can impart equal or greater damage to the product. Certain sterilization processes can initiate deep molecular changes within substances from which the products and their packaging are made. Reactions initiated by these processes can continue for many months following the treatment. Examples include radiation sterilization performed with ionizing isotopes or high voltage accelerators. Most sterilization processes affect the physical and chemical characteristics of materials. Some cause grossly visible changes in plastics, fabrics and metals. Others increase the amount of impurities that can be leached out of the product. Package integrity can be threatened through loss of adhesive bonds or increased fragility of the enclosing materials. The durability and integrity of the product may be also be altered in subtle ways which are not immediately evident. For long term implants, sterilization can drastically affect the safety and efficacy of the item. For pharmaceuticals, the pharmacological properties can be affected.

Pharmaceuticals and biologics such as antibiotics, blood products and vaccines present special restrictions because of the physico-chemical vulnerability of the active substances. Sterilization is habitually custom-designed for the product and elaborate validation studies are performed. Careful handling of these substances during fabrication is mandatory inasmuch as it controls the bioburden of the product. Sterilization techniques must not alter the product in such a way as to diminish its efficacy. Whereas these considerations are expected for pharmaceuticals and biologics, they are not always obvious to medical devices and products which are deemed to be without pharmacological effects. Examples of such products not only include items that are clearly recognizable as medical devices such as surgical instruments and catheters but also comprise semi-solids and fluids for specialized medical applications.

Examples of items that do not fit clearly into recognizable sterilization categories include non-medicated parenterals, certain types of wound care fluids and gels, irrigation fluids for surgery, hemostatic substances, surgical adhesives and gel-like products for intraoccular surgery. Within this class of product, there are some that are of mixed type; they include both solid components and semi-solids and gels or even liquids which are habitually sterilized as a composite. Such products present special challenges and are amongst the most demanding in terms of sterilization technology. Paradoxically, this class includes BREAST IMPLANTS.

Most medical consumables are sold in a packaged condition and the method of packaging varies according to the type and the end use of the materiel. Many sterilization processes are conducted on products that are packaged in their final state. Some products requiring high levels of sterility may be sterilized according to multiple processes performed stage-wise with intervening packaging steps. Different methods of sterilization may be employed for each step. For example, radiation sterilization may be used on some steps with a final sterilization of the packaged good using biocidal gas. Once subjected to a sterilization treatment, a correctly sterilized and packaged product ought not to revert to a less sterile state unless there are large populations of surviving micro-organisms which are restored to conditions favorable to their growth. This requires moisture and nutrients.

The most sophisticated forms of packaging are encountered for costly medical implants. Some types of packaging are hermetic, leading to well-controlled internal environments. Most are permeable. Classical examples include pacemakers, neurological shunts, intraoccular lenses and other solid objects intended for permanent residency in tissue. Most of these items demand multiple packaging and impose special techniques for sterile removal of the devices from the package.

Specialized forms of packaging are used for devices that have gel-like or fluid components. Such products are usually sterilized in stages and demand extreme care during production including multiple filtration to physically remove extraneous micro-organisms and solid debris. Some depend on entirely automatic production techniques conducted within controlled environments up to the time the containers are sealed.

Durability of packaged sterile goods is assessed on the basis of retention of the microbiological status of the product after sterilization. The packaging used is crucial and the expected durability performance can vary from several days to decades depending on materials used, the number of superposed packaging containers (multiple sterile container systems) and methods of bonding and assembling the package system. The gold standard is hermetic sealing using rigid packaging with permanent closures. Items packaged thus can remain indefinitely stable if the package itself does not disintegrate and if it were not that some substances within the packaged goods can act as nutrients for surviving micro-organisms. Thus, in spite of hermetic sealing, there are situations where semi-fluid medical products originally prepared in a nearly sterile way gradually revert to a microbiologically compromised condition, the substance itself acting as a consumable nutrient. Examples of this kind include viscoelastic gels intended for intraoccular surgery.

Sterilized products do not necessarily remain that way over time. Storage conditions affect retention of sterility level. Elevated moisture and the presence of certain gaseous substances can cause gradual increase in the population of incidental micro-organisms. Many countries require explicitly stated expiry dates for sterility retention claims. At first glance this policy would seem self-contradictory. In practice, it is desirable because most 'sterilized' products have surviving entities and many types of packaging do not control the environment of the sterilized object. Thus, surviving organisms may fortuitously reach conditions that allow growth or packaging integrity may be lost over time allowing ingress of extraneous viable entities.

Many types of sterilized products including bulk bandages, surgical disposables, catheters and other products with fleeting contact with tissue are sold in fragile, poorly designed packages. Deterioration of seals and worsening porosity in the package enclosure with handling expose the content to loss of sterility over time. Outright disintegration of brittle packaging becomes the ultimate limiting factor.

Storage time guidelines are occasionally published or included with product inserts. Such information rarely appears on outer labeling, leaving the user with the decision on usability of materiel that has been in storage. With reference to implants where substantial item costs are involved and where there it is traditional to order devices for individual patients shortly before use, the issue of storage time is rarely a consideration from the point of view of the institution. However, bulk inventory at the manufacturer or the distribution center, is a decisive factor. Accordingly, devices may be released from inventories long after fabrication, in particular if there are anomalies with the item or if demand is minimal. The dating of incoming consumables is therefore important for institutions and ideally manufacturers should include fabrication dates on the outer packaging. This is rarely done in North America. For less costly consumables purchased and inventoried in large quantities, storage time records are much more important and institutional protocols normally require that these items be kept track of to minimize storage time and consumed as soon as possible.

Aberrant Practices:

Commercial practices surrounding the marketing and distribution of medical products vary widely according to geographic area and distributor policies. It is widely known but rarely acknowledged that liquidation of medical consumables takes place. Redistribution of reclaimed items sold at a discount, given as 'physicians' samples' or released as promotional material takes place. Institutions frequently return surplus consumables or items they deem unsatisfactory for credit; materiel of this kind can reappear in commerce many years after their return. Some manufacturers and distributors allow removal of these items from their original packaging and reissue after repackaging and resterilization. These practices were widespread for plastic surgery products and for emergency care materiel up to the early-nineties. Unfavorable publicity surrounding the practice led to corrective measures in most industrialized countries but the practice may continue in smaller surgical centers subject to severe cost constraints.

Very few manufacturers and institutions openly condone extemporaneous resterilization to restore a product to the required sterility level. In principle, such practices can lead to acceptable products. However, the procedures are usually motivated by economic considerations. Extensively employed in the thirties and forties and still used in economically depressed geographic areas, this approach is no longer acceptable unless there is detailed and accurate information about the methodology used for resterilization. Furthermore, validation of the process has to be performed. Because of wide-ranging properties of medical consumables and the vulnerability of some to the actual process, there is no basis to assume that products can be resterilized reliably by standardized institutional methods. Validation of such processes can be as costly as the device itself and is rarely practical if only a few items are involved. Furthermore, biological residuals and contaminants on the products may exceed what can be accommodated by the sterilization process. Extemporaneous resterilization of single use consumables is therefore an unsanctioned practice and is particularly hazardous when performed on long term medical implants, least of all on devices which have entered the surgical field and may be contaminated by residual tissue and blood products.

Reconditioning of medical materiel at the point of use is performed increasingly in the context of cost containment policies. This may be done either by the institution or through subcontractors, sometimes of offshore origin and not subject to guidelines on 'good manufacturing practices'. Under these conditions, the microbiological status of the material cannot be reliably appraised within the economic constraints imposed by the circumstances. With reference to implantable devices, the practices are emphatically unacceptable. Yet, such practices were widespread in cosmetic surgery implants and in particular breast implants. Minimal information is available on the prevalence of these practices. Because of the unfavorable perception of such activities, there is reluctance on the part of organizations and institutions to accurately record recycling or even document the protocols employed. Thus, records surrounding recycling and resterilization of consumables are sparse and generally inaccurate. With the exception of high cost implants such as pacemakers, there is little published information on this activity.

Sterilization of BREAST IMPLANTS:

Breast implants are articles of commerce made in large numbers and sterilized in bulk after packaging, usually through exposure to biocidal gases. The efficacy and cleanliness of the process is strongly dependent on the condition of the devices at the time of sterilization. The amount of viable material, termed "bioburden", can vary widely. Non-viable material, including oils, proteinaceous films and extraneous production debris are usually present in significant amounts and can alter the sterilizability of the product. Large quantities of surface oils and hydrophobic substances can agglomerate micro-organisms and protect them from the action of the sterilization treatment. Breast implants filled with silicone gel/oils are particularly inappropriate products for many kinds of sterilization methods. The large amount of surface impurities and the extensive handling of the products during fabrication and packaging make them well suited for large populations of viable residuals.

Production conditions affect bioburden and contamination levels. The manufacturing of breast implants according to established technology is archaic and problem-riddled. Breast implants, because of their poor designs with closed compartments, the use of oily mixtures and their large rate of Production, are prone to production errors which impact on the reliability of sterilization and the quantity of extraneous substances created by the sterilization process.

Contamination of raw materials, production line errors and improper sterilization sequences are common. Failed sterilizations are widely encountered. Conventional remedial action is to resterilize the aborted batches. Multiple attempted sterilization creates unique problems including enhancement of impurities and increased toxicity from residuals. Aeration time, a key parameter for sterilization with biocidal gasses, must be drastically increased prior to usage as these gasses dissolve within the fluid and are retained tenaciously. Monitoring of residual gas entrapped within compartments and dissolved in oily filling material must therefore be monitored. In practice, this is rarely done.

Breast implants are not monolithic objects. They have multiple cavities and imperfections which can harbor viable and non-viable material. They are habitually considered as high bioburden items. Some styles are much worse than others, in particular multi-compartment implants and complex devices that incorporate remote filling ports, fabric fixation appendages and other features than increase the surface area and the complexity of the configuration.

Gross contamination of valves is found on many multi-lumen implants. Viable entities rarely survive the sterilization treatment in large numbers but survivors are habitually found in recesses and agglomerated in oily films. Even if rendered non-viable, they may remain as grossly visible protein films. They are most abundant in protected recesses, patch lap defects, valves and other surface irregularities that accumulate oils and solid particles. Some valve designs are special problem areas because they require silicone-based greases in the vestibule/port assembly. Easily contaminated grease-sealed valve systems are found on leaf, tubes and slip joints. Other designs incorporate complex cavities which are also prone to contamination. Plug-style valves with cap closures are prone to contamination during fabrication and become inevitably contaminated with biological material incidental to intrasurgical filling. Extreme contamination of these parts is habitually seen on implants removed from users, even after only a few days of well time. Contamination by finely divided solid particles is frequently visible on new, unused devices.

Other forms of contamination can affect the shell with manually assembled parts. Devices with foam coverings, multi-compartment valved implants, saline inflatable, and tissue expander can harbor micro-organisms and contamination introduced during production of individual parts, assembly and processing. It may be possible to remove these impurities through secondary decontamination processes but once assembled, the interior compartments become inaccessible. Thus, different levels of bioburden are likely to be encountered with the dominant amounts in interior compartments. Viable entities within closed compartments that later become filled with aqueous fluids have a privileged status and have a strong probability of surviving for many months following implantation. Residuals of this kind explain, in part, the rapid colonization of aqueous compartments in bi-lumen breast implants, saline inflatables, tissue expanders and penile implants filled with saline-based fluids.

Most medical implants undergo one or more thermal treatments during their production. On first examination, it would be expected that strong thermal treatments incidental to molding, extrusion, vulcanization, calendaring and sealing would impart sterility to the heated components. For reasons that remain unclear, this expectation is not supported. Colonies of viable micro-organisms have been observed to grow within raw materials, fabricated parts and trapped within bonded seams and laps in situations where heating took place. This suggests that viable entities encountered during production are very hardy and can reactivate following long dormant periods when the conditions become less hostile. Recovered implants showing this kind of contamination, visible with the eye unaided, are encountered. They suggest extreme production deficiencies and habitual uncleanliness of tooling as well as other violations of basic rules of production as they apply to medical materiel.

Viable entities entrapped within gel, oil, greases and elastomer can evidently survive sterilization treatments. They may remain dormant until moisture and nutrients become available. Upon implantation, they proliferate and exfoliate from the soft material causing blistering and visible growth within the material. Eventually they surface and may act as innoculae in surrounding tissue. Clinical impact of these hardy, uncommonly encountered micro-organisms is not assessed. They include microbacteria associated with rare clinical conditions which can revert to spores upon desiccation and remain dormant for decades.

Consequences of Colonization of the Implant Space:

Breast implants harboring viable entities are deemed to constitute a significant risk of infection. This issue is implicit in publications on saline inflatables and gel-filled implants where users suffered acute or chronic infective episodes. Product inserts for breast implants give a special sense to discussions on infection. The occurrences are deemed to reflect improper surgical procedures or misadventures unrelated to the sterility of the implant. There is a basis to question this assumption. Furthermore, surgical practices surrounding implantation of breast prostheses employ large quantities of assorted antibiotics both in the implant site and frequently within the aqueous compartments of the implants. Thus, clinicians expect a baseline of innoculae from implants and have empirically developed techniques hoping to circumvent the inadequacies of the products.

The clinical literature on breast implant usage documents a relation between acute and chronic infection in the periprosthetic area and rapid onset of contracture. Studies spanning from the late-seventies to the present document the finding of microbiological entities in the intracapsular space for users who suffer early and severe contracture. This Problem affects from thirty to as much as seventy percent of breast implant users depending on the authors of the published works. On this basis, it would appear logical to credit intrinsic contamination of breast implants by micro-organisms with the most frequently reported adverse reaction. Paradoxically, corrective measures to upgrade the microbiological safety of breast implants at the manufacturing level have not been implemented to a significant degree. Contamination of the surrounding space between the capsules and the implants by viable microorganisms may also originate from the user and micro-organisms from the ski may enter and populate the intracapsular space; some of these organisms are occasionally revealed in post-surgical workup when patients infect grossly. In most cases, atypical organisms are involved. Cultures and diagnostic stain studies are not sufficiently detailed and prolonged to confirm the presence of unfamiliar, slow-growing entities. The nature of the prostheses and their hydrophobic surface contaminants protects the innoculae, allowing the organisms to lodge within surface defects. This problem is acute for textured surface devices and devices incorporating complex leaf valves or assembly defects leaving spaces between parts. Capsule formation further protects the viable entities from natural body defenses and post-surgical antibiotics. This is also a common situation which leads to progressive contracture over a brief period of time. Focal colonization of capsules can produce even more spectacular contracture anomalies. In some cases, gross malformation and irregularities that are outwardly obvious are produced giving dramatic effect to the problem.

Secondary fibrosis of capsules as a result of low grade chronic intracapsular infection is documented in plastic surgery literature (publications - "The Fate of Breast Implants with Infections Around Them"; E.H. Courtiss, R.M. Goldwyn and G.W. Anastasi, Plastic Reconstructive Surgery, 63 (6) 812-816, 1979; "Acceleration of Capsule Formation around Silicone Implants by Infection in a Guinea Pig Model"; N. Kossovsky, J.P. Heggers, R.W. Parsons, M.C. Robson, Plastic Reconstructive Surgery, 73 (1) 91-97, 1984).

Textured surface implants appear significantly more prone to these problems; their capsules are more porous and generally more voluminous. They would therefore be expected to be a superior environment for proliferation of colonies and would allow significant populations of micro-organisms with a major output of metabolic toxins. They would constitute nearly ideal sites for clustered seromas and hematomas. Foam implants and textured surface prostheses have traditionally been perceived as resterilizable by analogy with devices with smooth walls. This perception is incorrect. All devices with complex porous surfaces become rapidly and irreversibly contaminated with fine particulates, fibers and emulsified substances upon contact with extraneous environments. Any attempt to wash or clean such products to restore them to an implantable condition is followed by drastic uptake of fine debris and dispersed oily substances within the pores.

The most salient examples of faulty product inserts include documents provided with foam-coated products. All product inserts explicitly allow point-of-use resterilization following extemporaneous washing of the items. Processes recommended for resterilization include steam sterilization with comparatively elevated temperatures. These chemically alter the foam and the adhesive. Gross recontamination of the foam pores with extraneous debris results from the cleaning process. The sterilization process further boosts the already elevated level of oil and gel impurities which are stored in the foam pores. The high temperature alters the foam and accelerates the resorption leading to early release of impurities intermingled with decaying foam. Because the release of debris takes place early in the implant history, this material concentrates at the implant interface prior to formation of capsules and thus significant dispersal of these impurities takes places. Such material subsequently lodges in portions of the breast distant from the capsule/implant interface.

Summary:

Sterilization technology is a well established sub-discipline based largely on empirical studies. It is sufficiently developed to yield reliable products devoid of large quantities of viable microorganisms. However, the breast implant manufacturing technology that has been used for the last decades is ill-suited to the technology. No corrective measures or detailed research has been undertaken in relation to the problem in spite of widespread clinical evidence that residual micro-organisms are major factors in breast implant adverse reactions. Such evidence is published, albeit sparingly, but is obvious even to the eye of an unsophisticated observer who has the opportunity to examine removed implants with internal fluid compartments. Since the outset, breast implants removed after unsatisfactory outcome have been returned to manufacturers in large numbers. Many of these devices clearly show evidence of gross colonization in vivo which can only be explained by assuming that the devices were inoculated incidental to production and/or packaging.

It is therefore inconceivable that these processes and their etiology are unknown to the manufacturing community. The lack of corrective measures is more puzzling inasmuch as colonized implants automatically doom the user to eventual complications that can only be addressed by explanting the offending devices and the surrounding tissue. The competence and the motivation of policy-making elements within the industry can therefore be questioned in the context of sterilization technology and microbiological product safety.