Assuring the Quality of Pharmacy-Prepared Sterile Products

Kenneth E. Avis, DSc
Emeritus Professor
The University of Tennessee
College of Pharmacy
Memphis, Tennessee

Any pharmacy that prepares sterile products must give top priority to quality assurance practices, to assure the safety and therapeutic efficacy of its extemporaneously prepared products. However, while every professionally committed pharmacist would agree that all pharmacy-prepared sterile products should be of high quality, not all have agreed on the level of quality required nor how it can be achieved. This lack of agreement may have been at least partly due to the fact that no profession-wide standard of practice had been promulgated. With the publication of two guidelines, the American Society of Hospital Pharmacists (ASHP) "Technical Assistance Bulletin on Quality Assurance for Pharmacy-Prepared Sterile Products" in 1993 and the United States Pharmacopoeia (USP) <1206> "Sterile Drug Products for Home Use" in 1995, the situation was alleviated. While not regulatory, both of these guidelines provide directions for setting quality standards and practices for achieving them. Both were published in draft form for comment before the final version was prepared. Therefore, the final form represents the thinking of not only the select committees that drafted them and the distinguished boards that approved them, but to some degree, of the profession at large. Their existence provides a point-of-reference for sterile products preparation practices--and a focus for this discussion.

An accepted reality today is that technicians generally perform most of the actual compounding procedures for sterile products in institutional settings. It has, however, been clearly stated by state and national boards of pharmacy that pharmacists are responsible, legally and ethically, for compounding and dispensing practices in their pharmacies. To be able to properly supervise technicians, pharmacists must be at least knowledgeable and as well-qualified in technical abilities as their technicians. This discussion, therefore, is applicable to both supervisory pharmacists and their staffs, pharmacists of technicians, who prepare sterile products.

Being alert to safety
Sadly, from time to time, tragic events spur a review of dispensing practices. Such an instance occurred quite recently, causing the FDA to publish a safety alert to hospital pharmacies (AJHP 1994;51:1427). The alert was a consequence of the death of two patients and the injury of two others, apparently from calcium phosphate precipitated in pharmacy-prepared total nutrient admixtures (TNAs). A subsequent survey, reported in a letter to the AJHP (1995;52:2727), revealed that a majority of the pharmacies preparing TNAs had made little or no change in their practices after the safety alert was published. If the survey truly indicated that pharmacists were not moved to review their procedures for possible needed corrections, this could be a serious indictment. It is to be hoped, rather, that they reviewed their procedures and found them in general compliance with the guidelines.

Both guidelines give recognition to the fact that dispensing of pharmacy- prepared sterile products can be divided appropriately according to the level of apparent risk inherent in the dispensing procedures. The ASHP and the USP guidelines use somewhat different terminology and descriptors, but each distinguishes three risk levels (Table). For simplicity, the ASHP system of designation (Risk Levels 1, 2, and 3) will be used in the following discussion.

FACTORS CONTRIBUTING TO HIGH-QUALITY STERILE PRODUCTS
In general, sterile products used for parenteral, ophthalmic, and select irrigation must be free from chemical and physical contaminants, accurately and correctly compounded, pharmaceutically elegant, pyrogen-free, and stable for their intended shelf-life. They must be packaged in a manner that will assure maintenance of their quality until used. For convenience, the key factors contributing to the preparation of sterile products of high quality can be divided into four categories: components, facilities, environmental control and operators.

Components
The majority of sterile products prepared in a dispensing pharmacy today utilize components that are clean, sterile, and pyrogen-free as purchased from a supplier. Such is intended for Risk Levels 1 and 2. Therefore, the pharmacist depends on the quality standards and reliability of the supplier. Responsibility for assuring the quality of the products used in processing rests squarely on the shoulders of the pharmacist-in-charge.

While it is generally not feasible to perform a personal quality audit of the supplier's operation, that may be an option to consider if there are no other ways to determine the quality standards for the products distributed by that supplier. Fortunately, this is not usually necessary. The reputation of an established supplier is often common knowledge. The Freedom of Information (FOI) Act makes it possible to request the latest FDA inspection report on the supplier's operation. This report will identify any prominent defects. It should be kept in mind, however, that even the best operation will likely have at least a few deficiencies; it is the magnitude, critical nature, and persistence of the cite deficiencies that should be evaluated. Asking fellow pharmacists about their experiences with the supplier also may give valuable insight into the quality of products supplied.

Certificates of quality. These may be requested from the supplier. They may include, for example, quality control test results from a typical batch of a currently used sterile product, encompassing qualitative and quantitative chemical purity, levels of particulate matter, and results of sterility and pyrogen testing. Or they may include results of tests for particulate level, sterility, pyrogen content, and critical physical defects for a lot of syringes. Such evaluation should be followed in the pharmacy at least by visual inspection of components as they are used--a simple but effective element of quality control.

Risk Level 3 envisions the use of raw materials that are neither sterile nor pyrogen-free. The extemporaneous compounding of morphine HCI solutions is often used as an example. In such instances, it is essential to obtain a certificate of quality analysis from the supplier for the chemical substance, since the pharmacy is usually not equipped or qualified to perform chemical analyses. Assuming that the certificate is judged to be reliable and the substance meets acceptable standards, such as those of the USP or National Formulary (NF), the pharmacist can then take the responsibility for using the compound. Subsequent compounding procedures must be developed so that the final product meets the standards required for a sterile product, including sterility, freedom from pyrogens, and acceptable particulate level.

Assuring that the product has the required characteristics--as a consequence of compounding and processing for Risk Levels 1 and 2-- is primarily a matter of maintaining the quality level "built into" the product by the commercial supplier. This is relatively easy to do, provided the pharmacist has available appropriate facilities and equipment and is both trained and motivated to meet the standards of excellence required. These factors will be considered later.

Risk Level 3 products. For these, the pharmaceutical characteristics must be produced as a consequence of the compounding and processing steps. Sterility must be achieved, usually by appropriate filtration through sterile, disposable, nonreactive, 0.2-um porosity membrane filter devices. Concurrently, particulate matter will be removed to very low levels and to below visible sizes. Pharmaceutical elegance, specifically clarity of the solution, will also normally be achieved with proper filtration techniques. Detailed concepts and techniques for filtration techniques. Detailed concepts and techniques for filtration have been reviewed by McKinnon and Avis; space does not permit their further discussion here. Removing pyrogens will be more difficult; the best approach is to obtain raw materials that are free from pyrogens as supplied. When pyrogens are present, appropriately charged filters may remove them, but determinations must be made to be sure that required molecules in the formulation are not also removed. A more complex technique is the use of ultrafiltration, which removes molecules selectively by size.

In all compounding procedures, the pharmaceutical quality of the right ingredients in the right amounts must be achieved. Compounding accuracy is a critical attributed, related to the techniques of the operator and the system of checking so common in pharmaceutical dispensing. However, its commonality must not lead to complacency; only rigid adherence to a validated che3cking process is acceptable. The more potent the formulation components and the more complex the compounding procedure, the more rigorous the checking system must be. Therefore, Risk Level 3 products will generally required the most rigorous checking system.

Compatibility and stability. Responsibility for the compatibility and stability of formulated products also rests on the pharmacist; achieving these qualities is difficult and sometimes frustrating. Detailed compatibility and stability information may not be readily available for extemporaneous compounding. Lacking the facilities to perform research and testing, the pharmacist is challenged to draw upon his/her basic chemical and physical knowledge, experience in compounding, and awareness of available literature resources. Probably the most widely used and best single reference is Trissel's "Handbook of Injectable Drugs." Other information may be available from the commercial supplier of a product component and from other literature resources such as "Remington's Pharmaceutical Sciences."

Unexpected compatibility problems may be visible immediately or within a few hours of compounding, but not all incompatibilities give visible evidence. All incompatibilities affect the stability of a preparation. However stability considerations are normally broader and include overall assurance that the activity and chemical/physical integrity of the formulation is maintained until the product is administered to a patient. Within a hospital this shelf-life is usually quite short--ie, 24 to 48 hours. For products prepared for home-care patients, the shelf life is usually required to be at least 30 days. When products are known to have limited stability, storing under refrigeration or freezing probably will extend the shelf-life. However, the effect of freeze- thaw processing on the product must be carefully evaluated since some products, especially the protein-containing biotechnology products, may be adversely affected.

Facilities The facilities in which the preparation of sterile products is to be performed must be designed and operated in a manner conducive to achieving/maintaining the aseptic characteristics of the finished product. While some lightening of the standards for facilities used in the preparation of Risk Level 1 products is permissible, usually it is most reliable to meet the stringent design requirements for Risk Level 3 products. The critical area for all three risk levels should be a Class 100 (USP's <1116> proposed Class M3.5) environment. This means that the maximum count allowable for airborne particles 0.5 um and larger is 100/ft3 or 3530/m3, and the maximum for viable organisms, 3 colony- forming units (cfu)/m3 air. It is the surrounding controlled areas that will differ, largely because of the greater space requirements for larger volume or greater complexity of operations for Risk Levels 2 and 3 products.

The facilities may vary from a single high-efficiency particulate air (HEPA)- filtered laminar air-flow workbench (LAFW) providing a Class 100 environment (Figure 1) that is protected from uncontrolled surroundings by a wall, plastic curtain, or other barrier, to a multiroom, controlled area occupying several hundred square feet, with one or more entire rooms as critical areas. Figure 2 shows a moderate-sized controlled area floor plan from USP <1206>.

The surfaces of all ceilings, walls, floors, shelving, cabinets, and work surfaces in the buffer room and anti-room should be smooth, impervious, free from cracks and crevices, and nonshedding, making them easy to clean and sanitize. Junctures of ceilings to walls, walls to walls, and floors to walls should be coved or caulked to make them easier to clean. There should be no dust-collecting ledges, pipes, or similar surfaces. Work surfaces should be constructed of durable, smooth, and impervious materials, such as stainless steel or molded plastic. Carts should be of stainless steel wire or sheet construction with good quality, cleanable casters, and should be restricted to the controlled area. The key equipment unit is the LAFW, designed to continuously sweep the work area with HEPA-filtered air at a velocity of 90 fpm+20%. The 99.97% efficiency of an HEPA filter in removing particles of 0.3 um and larger should render the air stream clean and approaching sterility, if properly validated. Still, this gentle air flow velocity can easily be overcome with adverse air currents, even by the expelled breath from operators talking; thus, the critical work area must be protected with barrier and from inappropriate activities of personnel (to be discussed later). In Figure 2 the walls of the buffer room create the barrier, but it could be as simple as a plastic curtain surrounding the LAFW, hung from the ceiling and extending down to within a foot or so of the floor. The HEPA filter should be protected from damage during use and its efficiency validated at least annually. Vertical LAFWs should be used to protect the product and also the operators when toxic chemicals or other toxic substances are being processed.

The level of cleanliness in the controlled area surrounding the critical area is crucial since, as noted, the LAFW has limited capacity to prevent the ingress of contamination from its surroundings, including, among other things, the in and out movement of supplies. Since such movement is essential for operations, the controlled area must provide progressive cleanliness control as the critical area is approached. Figure 2 shows this being achieved by the barriers, the distance, and the increased cleanliness levels from the anteroom through the buffer room. Further, clean airflow should be outward from the critical area through the buffer room and through the anteroom by means of cascading differential pressures, starting with the highest pressure from HEPA-filtered air in the buffer room. The source of this HEPA-filtered air can be from externally supplied LAFWs if the controlled area is of limited size. For larger facilities, additional or alternative HEPA-filtered air supply into the buffer room through a building HVAC system will usually be required.

These or similar structural design considerations, along with planned cleaning programs, sanitizing of all surfaces, and traffic control of personnel and supplies, should make it possible to protect the critical area so that the requirements for processing Risk Levels 1, 2, and 3 products can be met. For Risk Level 1 processing, minimal facilities might consist of an LAFW and a small enclosed controlled area combining the activities of the buffer room and the anti-room.

It should be mentioned that a new approach to facility design, recently introduced in the United States, has been used for some time in institutional practice in England and other European countries. The key equipment unit is an isolator, such as shown in Figure 3. Basically the unit isolates the Class 100 critical area from its surrounding controlled area by sealing the unit after cleaning and sterilization. Access is provided for personnel through glove ports or half-suits sealed in the walls with supplies introduced through "pass- thru" chambers. The advantages of such a system are that the critical area can be sterilized, not just sanitized; personnel preparation and gowning requirements are greatly reduced; and the level or requirements for the surrounding controlled area is reduced. The most apparent problem is the contamination risk associated with the introduction of supplies into the isolator and the removal of product. In my opinion, however, the latter problem should be solvable, and the advantages warrant optimistic consideration for processing of Risk Levels 1, 2, and 3 sterile products.

Environmental control
Proper utilization of the facilities described is fundamental to adequate control of the working environment, with the ultimate focus on the critical area. However, without corollary support of the controlled area, the LAFW alone, with its acknowledged efficiency, would be inadequate to provide a critical work area that could assure the sterility of the product in any of the three risk levels.

Since, by definition, a HEPA filter will deliver an air stream that has had particles of 0.3 um and larger removed with an efficiency of 99.97%, there is only a 0.03% probability of particles passing through, a small portion of which could be microorganisms. Therefore, the risk of any microbial contaminant in that airstream gaining ingress to a product is very low, particularly for Risk Level 1 products. The operational problem is to prevent contaminants from entering the critical area; such an effort constitutes environmental control-- keeping the critical area at least a Class 100 environment. Environmental control control encompasses several areas:

Cleaning and sanitizing. Surface contamination can be expected, even if it is not visible, and even in the LAFW. Therefore, written standard procedures should be developed and followed for cleaning and sanitizing all surfaces within the controlled area. Cleaning should be performed with a mild detergent in purified water using a nonshedding, absorbent wipe or sponge. This should be followed by wiping the surfaces with a recognized effective sanitizing agent (disinfectant). These products have been reviewed by the Parenteral Drug Association (PDA) Task Force on Decontaminating Agents. Alternatively, a commercial agent can be used, sometimes combined with a a detergent, provided adequate evidence of effectiveness is available. To avoid the possible development of resistant strains of microorganisms, it is recommended that the type of agent be rotated approximately every 3 months.

Cleaning in the LAFW may be done with a nonshedding wipe or sponge dampened with Water for Injection (WFI), with or without a mild detergent. This step should be followed by sanitizing, most often with sterile-filtered 70% isopropyl alcohol (IPA). Alternatively, cleaning and sanitizing may be accomplished with IPA alone, at least at the beginning and ending of each shift and whenever spillage occurs. All shelving, supply carts, and countertops in the remainder of the controlled area should be cleared of supplies and then cleaned in a similar manner at least weekly in the buffer room and at least monthly in the anteroom. Cleaning should be followed by wiping with a sanitizing agent more aggressive than IPA. Floors in these areas should be cleaned and sanitized daily, working from the cleanest area outward. The detergent and/or sanitizing agent solution should be replaced with fresh solution at frequent intervals during the cleaning. All reusable cleaning tools should be restricted to the controlled area and thoroughly cleaned and sanitized after each use.

Traffic control. The flow of supplies and personnel through the controlled area for operations in the critical area must be rigidly controlled to prevent carrying contamination inward. No personnel should be allowed to approach the LAFW unless properly gowned and adequately trained and validated. All supplies should be externally cleaned and sanitized during the moment through the controlled area. The outward movement of product is normally relatively problem-free.

Supplies should be uncartoned, cleaned, and sanitized at the entrance of the controlled area. Figure 2 illustrates an arrangement in which supplies would be brought into the anteroom external to the demarcation line. At this point, they would be uncartoned, cleaned, sanitized and transferred to a clean cart restricted to the controlled area. This step serves as a barrier to many of the natural contaminants on the outside of large volume injection (LVI) bags, vials, syringe pouches, transfer set packages and other required supplies.

A further transfer barrier step should occur as supply items are introduced into the LAFW. Whenever possible, an external wrap would be removed (such as LVI outerbags and syringe pouches) at the edge of the LAFW. Vials and other items not packaged in an outerwrap should be carefully sanitized by wiping with a wipe dampened with a sanitizing agent, most commonly IPA. The supply items introduced into the LAFW should be limited to those required for the planned procedure and should be arranged so as not to obstruct the HEPA airflow pattern and to provide for efficient processing--that is, to the right and left of the work site in a horizontal and around the perimeter in a vertical flow workbench.

These barrier steps during the introduction of supplies should be recognized as only sanitizing, not sterilizing, steps, and their effectiveness depends on the techniques of the operator and on the sanitizing agent used. Any residual contaminants on the surfaces of supply items may be transferred to the sterile gloves of an operator and then be present for possible touch contamination transfer to the product. This risk of contaminating a product will increase progressively from Risk Level 1 to 3 products.

Operators. Operators in the controlled area should be limited to those adequately trained and validated for aseptic processing and to the minimal number required for the planned procedures. Since the human body is constantly emitting particles, many of which are viable organisms, an effort must be made to reduce the ingress of these emissions into the controlled area but, particularly, into the critical area. This is accomplished by good personal hygiene, thorough washing/sanitizing of hands, following good aseptic practices (GAPs, to be discussed later), and by donning gowns to confine the emissions as much as possible.

Testing. While all the elements so far mentioned, pursued with dedication, should provide an environment under control, a testing program should be developed to verify that the control is achieved and maintained. The focus of testing should be on detecting the presence of microbial contaminants in the environment. Both surface testing, for the deposit of microorganisms on exposed surfaces over time, and air-volume sampling, for microorganisms suspended in the air, should be performed. The USP <1206> has described a testing program involving surface sampling with contact (Rodac) plates and air sampling with settling plates and surface-to-agar (STA) sampling. Schneider has given additional details of an environmental monitoring program. These references should be consulted for further details.

In principal, baseline (minimal) microbial counts should be determined when the environment is under control. A monitoring program should then be designed to detect loss of control evidenced by increases in the microbial counts. Such increases signal the need to determine the cause and correct it.

Operators and their training
The preceding discussion has stated several times that personnel involved in carrying out GAPs must be adequately trained and the effectiveness of the training validated. In fact, many would state that this is the most significant factor contributing the assurance of quality sterile products, for personnel are recognized as the primary source of contaminants, both viable and nonviable, emitted into the controlled environment. Therefore, operators must be taught to understand this natural phenomenon and how they may control this emission while performing their GAPs. Considerable information regarding proper training will be found in the ASHP and the USP guidelines. The following covers some sailent points.

Pharmacists and technicians who perform the operations required for the preparation of sterile products in a pharmacy must not only know and practice the manipulative techniques required, but they should understand something of the body of knowledge supporting the GAP's. One of the objectives of training is to transmit a basic body of knowledge, including the characteristics required of a sterile dosage form of a drug, the reasons for the high standards of purity for such products, quality control measures that apply, the facilities required, the environmental requirements for processing, and the role of operators in performing GAP's.

Training should make clear that these dosage forms must have the highest level of quality and purity of all dosage forms because they are given by injection, infusion, irrigation, or opthalmically. Thus, each of the routes utilized for sterile products deposits the drug directly within body tissues or with direct access to them. The first line of defense of the human body against the invasion of toxic substances--the intact skin and mucous membranes--is thereby circumvented. The secondary body defenses have much less capacity to neutralize the effects of toxic substances. Therefore, to avoid clinically adverse effects, toxic substances must not be present in administered sterile products. Trainees must be taught the significance of this fact and the importance of developing GAPs capable of keeping sterile products free from toxic contaminants. They should be instructed in the nature of contaminants and the means for achieving the required level of purity, maintaining stability during the required shelf-life of the product, and evaluating the required characteristics.

Quality control measures. Operators should be familiar with quality control tests that may be required; most often, they will have to know how to obtain the needed tests through outside laboratories and then how to evaluate the results obtained. Detailed information may be found in "Parenteral Quality Control" by Akers and Guzzao. These measures would include chemical tests for stability, physical tests for particulate content, and biologic tests for sterility and pyrogens. It must be remembered that, because of the short shelf-life for products used for institutionalized patients, tests results on a specific product may not be available before the product is administered. In such instances, test results are used to validate the process and not the specific product.

Pharmacists should also be sufficiently familiar with the principles of sterilization to be able to work with technicians who perform autoclaving or hot-air sterilization of supplies or products, whether in the pharmacy or elsewhere in the institution. The validation of these processes for their lethal effect is highly critical and requires considerable expertise.

Facilities required. While pharmacists and technicians are not expected to be engineers, they should know the implications of the specifications for facilities on the GAPs they must perform. Therefore, they must be able to work with the guide engineers in achieving and maintaining the facilities specifications required. This includes the selection of equipment (for example, an LAFW) from external suppliers or working with in-house engineers to assure proper clean air flow into the controlled area.

Environmental requirements. An understanding of some engineering principles is needed to achieve the required environmental standards. For example, an understanding of the dynamics of air flow through an HEPA filter to achieve laminar air flow and the clean sweep of the critical area is essential for its proper utilization. It is also necessary to know how to achieve the air- pressure differentials to produce the cascading effect from the buffer room out through the less-clean anteroom (see Figure 2).

The use of barriers to interrupt the ingress of contaminants inward toward the critical area must be understood, whether these are physical barriers such as walls or curtains or interruption barriers (i.e., removing supply items from a cart, cleaning and sanitizing, and transferring to another restricted-area cart). Another interruption barrier is the washing of hands and the donning of a clean uniform before entering the buffer room. The selection of the sanitizing agent must be based on knowledge of the antimicrobial action of the agent and the need for rotation of agents over time. A detailed survey of the use of such agents should be consulted (such as the PDA Task Force on Decontamination Agents). In addition, trainees must have a basic understanding of microbiology. They need to know that microorganisms are ubiquitous and therefore must be assumed to be present in the work environment, even in the critical area. They must know that these organisms will multiply rapidly (about every 20 minutes) by binary fission when moisture, the proper temperature, and nutrients are present.

Operators should understand the principles of environmental evaluation--ie, how to determine the effectiveness of the environmental control used. This means knowing and selecting methods for detection of viable microorganisms in the environment, what the methods selected will detect, how samples should be gathered and incubated, proving that any viable microorganisms present will grow, and what the results signify--including when and if action is required. The fundamentals of such a program are reviewed in PDA's Technical Report No. 13. The USP has proposed a microbiologic evaluation and classification of cleanrooms, which should be considered.

Performing GAP's. Typically, manual procedures by human operators are used in the individualized or small-scale preparation of sterile products in a dispensing pharmacy for Risk levels 1 and 2 products. A degree of automation has been introduced with the advent of mixing pumps and automated measuring devices for repetitive compounding, such as the addition of small-volume additives to large-volume TNAs. However, operators must set up such devices, connect fresh stock containers, fill the final product containers, and generally monitor the operation. Risk level 3 products are particularly exposed to the environment and to operators.

Because of the inherent discharge of viable and nonviable particles from the body of operators (as many as 1 million particles of 0.3um and larger per min. with average arm and upper-body movement from a sitting position dressed in a long-sleeved, nonshedding coat), serious efforts must be made to control this discharge. Means used include gowning, designed to confine most of the discharge within the uniform; planning movements while performing GAPs to minimize propelling particles from the body; and removing human beings as far as possible from the critical area. One of the most salient advantages of isolators is the fact that the bodies of operators are isolated from the critical area by the use of sealed rubber-glove ports and half-suits.

The generally accepted uniform for operators working at an LAFW in either a sitting or standing position would be clean hair cover, face mask, long-sleeved (with elastic or snaps at the wrists) nonshedding knee-length coat, shoe covers, and sterile latex gloves. Working at an isolator, the operator normally would wear only a pharmacy -style coat and possibly, a hair cover. An explanation of the reasons for these differences in gowning should be part of the body of knowledge transmitted during the training program.

The following lists some of what should be "second nature" to be student/operator after training:

  1. Practice good personal hygiene, be organized and level-headed.
  2. Be healthy, without eczema or other skin rashes and free from allergies or other conditions causing sneezing or coughing.
  3. Wash hands and arms thoroughly or disinfect with foamed alcohol.
  4. Put on uniforms properly, avoiding contaminating the outside of the clean/sterile uniform components.
  5. Replace a uniform or parts of a uniform that become contaminated while gowning or working.
  6. Put on sterile latex gloves as the final gowning step.
  7. Sanitize all internal surfaces of the LAFW (except the HEPA filter face) with an appropriate sanitizing agent, usually IPA.
  8. Sanitize latex gloves (usually with IPA) as frequently as necessary while performing GAPs to maintain the aseptic condition of the outer surfaces.
  9. Replace gloves with new sterile ones if they become punctured or torn.
  10. Move with slow, smooth, gentle motions.
  11. Do not talk unnecessarily.
  12. Do not disrupt HEPA-filtered laminar air flow within the critical area.
  13. Do not interpose arms or any other nonsterile object above a critical site in vertical laminar air flow (VLAF) or behind a critical site in horizontal laminar air flow (HLAF).
  14. Do no spray or splash disinfectants where the liquid might enter a product container or reach other product contact sites.
  15. Do not introduce any packages intothe buffer room unless they have been adequately sanitized or sterilized externally.
  16. Minimize in and out movement at the LAFW.
  17. Arrange sterile supply items in the critical area so as not to interrupt the laminar air flow and to provide for efficient processing of the product(s).
  18. Resanitize gloves with IPA after handling any package if the outside had uncertain sterility or surfaces such as switches of mixing pumps.
  19. Cooperate with other operators and mutually assist in maintaining proper GAPs.
  20. Pass through doorways, plastic curtains, or other passageways slowly and carefully to minimize the generation of wild, potentially, contaminating air currents.
  21. Do not leave open vials, tanks, or other critical sites exposed to the environment during breaks or other delays in operation.
  22. Inspect all supply items before using and the finished product after preparation for evidence of defects.
  23. Remove used supply items and clean/sanitize work area as needed.
  24. Prepare and apply appropriate labels and complete documents away from the critical area or, preferably, pass product outside so that a second person can perform the paperwork.
  25. Remove used uniforms carefully to avoid distributing accumulated body contamination before exiting the gowning room.
  26. Leave the HEPA filter blower operating at all times.

SUMMARY
This discussion has highlighted the requirements for assuring the high quality, primarily but not exclusively the sterility, of sterile products prepared in a dispensing pharmacy. Proficient orchestration of the varied elements discussed is essential, but even under the best conditions, only a probability of sterility can be claimed, usually a sterility assurance level (SAL) of about 10- 3 (1:1000). A better SAL is desirable and is probably achievable with Rise Level 1 products, but only dedicated attention to the pursuit of the elements discussed can assure the achievement of an SAL of 10-3 for Risk Levels 2 and 3 products. Such a level of quality, while acceptable because of the limits of current technology, should be viewed as a challenge to make future improvements.