Compounding Sterile Preparations, 3Rd Edition

21 Secondary Engineering Controls E. Clyde Buchanan

Introduction Functional Requirements Air Cleanliness CSP Microbial Contamination Risk Levels Hazardous Drugs Radiopharmaceuticals Allergen Extracts Immediate-use Provision Proprietary Bag and Vial Systems Other Regulatory Requirements for Facilities Buffer Area and Ante-area Heating, Ventilation, and Air Conditioning (HVAC) Surface Characteristics Placement of Equipment and Supplies Environmental Sampling and Testing Cleaning and Disinfecting Planning the Sterile Preparation Facility Strategic Master Facilities Plan Existing Facility Functional Program Architectural Schematic Plan Construction Contract Construction Commissioning for Occupancy Facility Maintenance Cleaning and Disinfecting Re-Certification Environmental Sampling and Testing Corrective Actions Summary References Compounding Sterile Preparations Introduction Functional Requirements

Regulatory standards and professional guide- Functional requirements follow USP Chapter lines (see Chapter 1 and Appendixes) require <797> because this is the enforceable stan- that pharmacists evaluate their sterile com- dard toward which most pharmacists strive. pounding facilities. Standards and guidelines Anti-areas and buffer areas or cleanrooms are specify that sterile preparations be compound- known collectively as “secondary engineering ed in an area separate from other pharmacy controls” because they provide the controlled activities. The most prominent standard, USP environments in which primary engineer- Chapter <797>, Pharmaceutical Compound- ing controls (laminar air flow workbenches, ing—Sterile Preparations, requires that most biological safety cabinets and compounding sterile compounding be done within an ISO isolators) are placed. Class 5 primary engineering control that is properly placed in a buffer area supported by 1 an ante-area Chapter <797> stresses that Air Cleanliness employee training and evaluation on garbing, hand cleansing, maintaining aseptic technique To follow USP Chapter <797>, pharmacists in an ISO Class 5 environment and disinfect- must understand controlled environment clas- ing gloves are the most important determi- sifications. For nearly 40 years, U.S. Federal nants leading to compounded preparations Standard 209 (FS 209) defined air cleanli- that are free from viable microorganisms and ness in contamination control,2 but FS 209 pyrogens. However, for primary engineering has been retired by the U.S. General Services controls to work properly (see Chapter 4) and Administration3 in favor of the internation- for personnel to maintain aseptic technique, ally-accepted definitions for cleanrooms and a clean compounding area is mandatory. clean zones promulgated by the International Further, Chapter <797> sets forth standards Organization of Standardization (ISO).4 See for handling hazardous drugs to protect the Table 21-1. compounder and the environment from contamination with toxic substances. This chapter explains the functional re- CSP Microbial Contamination Risk Levels quirements of a sterile compounding area, how to plan new sterile compounding areas or to For the most part, USP Chapter <797> sets alter existing ones, and how to purchase, vali- standards according to microbial contamina- date and certify sterile compounding areas. tion risk levels. The appropriate risk level—

Table 21-1. International Organization of Standardization (ISO) Classification of Particulate Matter in Room Air as Limits in Particles 0.5 Microns and Larger per Cubic Meter (Current ISO) and Cubic Feet (Former FS 209E)2

Class Name Particle Counts Per ISO Class U.S. FS209E ISO, m3 FS209E, ft3 3 Class 1 35.2 1 4 Class 10 352 10 5 Class 100 3520 100 6 Class 1000 35,200 1000 7 Class 10,000 352,000 10,000 8 Class 100,000 3,520,000 100,000

Source: Adapted by USP from the Federal Standard 209e, General Services Administration, Washington, DC 20407 (September 11, 1992) and ISO 14644-1:1999 Cleanrooms and associated controlled environments—part 1: Classification of air cleanliness. 260 Chapter 21 Secondary Engineering Controls

low, medium, or high—is assigned according in USP Chapter <797> or is a laminar airflow to the corresponding probability of contami- workbench (LAFW) or a biological safety cabi- nating a CSP with (1) microbial contamination net (BSC) that cannot be located within an ISO (e.g., microbial organisms, spores, endotoxins) Class 7 buffer area, then only low-risk level and (2) chemical and physical contamination nonhazardous and radiopharmaceutical CSPs (e.g., foreign chemicals, physical matter).1 pursuant to a physician’s order for a specific Chapter <797> applies more stringent facility patient may be prepared, and administra- requirements to high risk level compounding tion of such CSPs must commence within 12 as compared to low- and medium-risk com- hours of preparation or as recommended in pounding (see Table 21-2). the manufacturers’ package insert, whichever is less. Low-risk level CSPs with a 12-hour or less beyond-use date (BUD) must meet all four Low-Risk Level CSPs with 12-Hour or Less of the following criteria1: Beyond-use Date If the primary engineering control (PEC) is a l PECs (LAFWs, BSCs, CAIs, and CACIs), compounding aseptic isolator (CAI) or a com- must be certified and maintain ISO Class pounding aseptic containment isolator (CACI) 5 as described in USP Chapter <797> for exposure of critical sites and must be in that does not meet the requirements described

Table 21-2. Secondary Engineering Control Requirements by USP Chapter <797> Risk Level* Low Risk ● Ante-area—An ISO Class 8 (see Table 21-1) or cleaner area where personnel hand hygiene and garbing procedures, staging of components, order entry, CSP labeling, and other high-particulate-generating activities are performed. ● Buffer area—An ISO Class 7 (see Table 21-1) or cleaner area where the primary engineering control is physically located. Activities that occur in this area include the preparation and staging of components and supplies used when compounding CSPs. ● Ante-area and buffer area may be separated by a line of demarcation or by a physical barrier like a wall, door, and pass-through. ● Buffer area must have at least 30 air changes per hour (ACPH), or as little as 15 ACHP if a laminar air-flow workbench provides as much as 15 ACHP. ● HEPA-filtered air must be introduced at the ceiling and air return vents should be mounted low on the walls. ● A temperature of 20 degrees Celsius (68 degrees Fahrenheit) or cooler should be maintained by the heating, ventilation, and air conditioning system. ● Surfaces of ceilings, walls, floors, fixtures, counters, and cabinets in the buffer area must be smooth, impervious, free from cracks and crevices, nonshedding, and resistant to damage by disinfectants.

Medium Risk Same as low-risk level.

High Risk Same as low-risk level except that: ● ante-area must be physically separated from the buffer area by a wall, door, and pass-through.

*Source: U.S. Pharmacopeial Convention. Chapter <797> Pharmaceutical Compounding: Sterile preparations. http://www.usp.org/USPNF/pf/general Chapter797.html. Accessed on March 3, 2008. 261 Compounding Sterile Preparations

a segregated compounding area restricted that protect healthcare workers and other per- to sterile compounding activities. sonnel in the preparation and storage areas.1 l The segregated compounding area cannot This means not just the sterile compound- be in a location that has unsealed win- ing areas but where ever hazardous drugs dows or doors that connect to the outdoors are received, stored, handled, compounded or high traffic flow, or that is adjacent to or transported. Hazardous drugs must be construction sites, warehouses, or food stored separately from other inventory so preparation, etc. as to prevent contamination and personnel l Personnel must follow cleansing, garbing exposure. Many hazardous drugs have suf- and other personnel procedures described ficient vapor pressures to allow volatilization in USP Chapter <797> prior to compound- at room temperature; thus storage should be ing. Sinks should not be located adjacent within a containment area such as a nega- to an ISO Class 5 PEC. tive pressure room. The storage area should have sufficient general exhaust ventilation, at l The USP Chapter <797> specifications in least 12 air changes per hour (ACPH), to dilute cleaning and disinfecting the sterile com- and remove any airborne contaminants.1 The pounding areas, personnel training and USP’s expert Sterile Compounding Committee competency evaluation of garbing, aseptic 5 work practices and cleaning/disinfection (SCC) states that the negative pressure stor- procedures, and viable and nonviable en- age conditions protect personnel outside the vironmental air sampling must be followed compounding area from hazardous drug ex- as described in Chapter <797>. posure at a minimal risk of ingress of airborne contamination. Further, there may be no need See Table 21-3 for a summary of secondary en- for an additional negative pressure room for gineering controls required for each classifica- hazardous drug storage. That is, smaller vol- tion of compounded sterile preparation (CSP). ume hazardous compounding facilities can simply store the hazardous drugs in the che- CAIs and CACIs must be placed in an ISO motherapy compounding buffer room, which Class 7 buffer area unless they meet all of the should already meet the minimum criteria for 1 following conditions : hazardous drug storage.5 l The isolator must provide isolation from All hazardous drugs must be prepared in a the room and maintain ISO Class 5 during biological safety cabinet (BSC) or a compound- dynamic operating conditions, including ing aseptic containment isolator (CACI). The transferring ingredients, components, and ISO Class 5 BSC or CACI must be placed in an devices into and out of the isolator and ISO Class 7 buffer area that is physically sepa- during preparation of CSPs. rated (i.e., a different room from other prepara- l Particle counts sampled approximately 6 tion buffer areas) and optimally has not less to 12 inches upstream from the critical than 0.01-inch water column negative pressure exposure site must maintain ISO Class 5 to adjacent positive pressure ISO Class 7 or bet- levels during compounding operations. ter ante-area, thus providing inward airflow to l Not more than 3520 particles (0.5 mi- contain any airborne drug. A pressure indicator crons and larger) per cubic meter can be must be installed that can be readily monitored counted during material transfer, with for correct room pressurization. The BSC and the particle counter probe located as near CACI should be 100% vented to the outside air to the transfer door as possible without through HEPA filtration.1 obstructing the transfer. There is no requirement for a separate anteroom for the negative pressure ISO Class 7 Compounding personnel must obtain docu- buffer room. The same ante-room can be used mentation from the manufacturer that the for both non hazardous and hazardous buffer CAI or CACI will meet the conditions above rooms. The difference in cost of making the when located in environments where the back- ante-room ISO class 7 instead of ISO class 8 ground particle counts exceed ISO Class 8.1 is minimal. For example, using a relatively large ante-room size of 10 foot x 10 foot with Hazardous Drugs an 8-foot ceiling (total volume of 800 cubic feet) the difference to go from 20 ACPH (266 USP Chapter <797> states that hazardous cubic feet per minute [CFM]) as appropriate drugs must be prepared only under conditions for an ISO class 8 room to a minimum of 30 262 Chapter 21 Secondary Engineering Controls

Table 21-3. Summary of Secondary Engineering Controls Required for Each Classification of Compounded Sterile Preparation (CSP)

Type of CSP per USP ISO Class Requirement Segregated Compound- Chapter <797> Ante-Area Buffer Area ing Area Low risk Class 8 positive pressure to Class 7 positive pres- main pharmacy and either sure to ante-area physically separated from buffer area by a wall or by displacement air flow Medium risk Class 8 positive pressure to Class 7 positive pres- main pharmacy and either sure to ante-area physically separated from buffer area by a wall or by displacement air flow High risk Class 8 positive pressure to Class 7 positive pres- main pharmacy and physi- sure to ante-area cally separated from buffer area by a wall Low risk with less than Not required Not required Demarked area or 12-hour BUD* room restricted to preparing low-risk CSPs with 12-hour or less BUD Immediate use with one hour or less BUD Not required Not required Not required Hazardous drug Separate Class 7 positive Separate Class 7 pressure to buffer room negative pressure buffer room Radiopharmaceuti- Class 8 or better for Low-risk with 12-hour cal Tc99m or Mo99 or less BUD radiopharmaceutical with line of demarcation Allergen extract appropriately preserved for intradermal or Not required Not required Not required subcutaneous injection Proprietary bag and Not required Not required Not required vial system

*BUD, beyond-use date.

ACPH (399 CFM) for an ISO class 7 space ing area must maintain a minimum negative only requires 133CFM. In either case, all of pressure of 0.01-inch water column and the supply air can be delivered through one have a minimum of 12 ACPHs.1 In a health HEPA filter.5 care institution that prepares a low volume If a CACI that meets the USP Chapter <797> of hazardous drugs, the use of two tiers of requirements above, is used outside of an ISO containment (i.e., a closed-system transfer ® Class 7 buffer area, the separate compound- device [e.g., PhaSeal ] with a BSC or a CACI that is located in a non-negative pressure 263 Compounding Sterile Preparations room) is acceptable.1 The decision as to what is ments, regardless of whether compounded by “low volume” is left to the sterile compounding pharmacist, physician or other trained person- institution. nel. Allergen extract compounders must follow specified hand cleansing, garbing and aseptic techniques and labeling standards.1 Therefore, Radiopharmaceuticals suitable space is required for compounding and USP Chapter <797> specifies that radiop- storage of equipment, supplies and finished harmaceuticals must be compounded using preparations. appropriately shielded vials and syringes in a Chapter <797> mandates no standards for properly functioning and certified ISO Class 5 allergen extract compounding facilities. How- PEC located in an ISO Class 8 or cleaner air ever, the Joint Commission™ does have facil- environment to permit compliance with special ity standards for medication preparation (see handling, shielding, and negative air flow re- other regulatory requirements below). See also quirements. Storage and transport of properly Chapter 9 on Allergen Extracts as CSPs. shielded vials of radiopharmaceutical CSPs may occur in a limited access ambient environment without a specific ISO class designation.1 Immediate-use Provision Technetium-99m/molybdenum-99 genera- USP Chapter <797> restricts the immediate- tor systems must be stored and eluted under use provision to those situations where there conditions recommended by manufacturers is a need for emergency or immediate patient and applicable state and federal regulations. administration of a CSP, e.g., cardiopulmonary Such generator systems must be eluted in an resuscitation, emergency room treatment, prep- ISO Class 8 or cleaner air environment to per- aration of diagnostic agents, or critical therapy mit special handling, shielding, and air flow where the imposition of low-risk operating con- requirements. Radiopharmaceuticals prepared ditions subjects the patient to additional risk as Low-Risk Level CSPs with 12-hour or less due to delays in therapy. When CSPs meet all six beyond-use dating must be prepared in a segre- immediate use conditions, Chapter <797> man- gated compounding area. A line of demarcation dates no standards for compounding facilities. defining the segregated compounding area must However, the Joint Commission™ does have be established. Materials and garb exposed in facility standards for medication preparation a patient care and treatment area must not (see other regulatory requirements below). cross a line of demarcation into the segregated compounding area.1 Proprietary Bag and Vial Systems See Chapter 8 on Radiopharmaceuticals as CSPs. USP Chapter <797> allows an exemption to risk level facility standards for proprietary bag and vial systems. The sterility storage and stability Allergen Extracts beyond-use times for attached and activated The USP’s expert Sterile Compounding Com- (where activated is defined as allowing contact mittee (SCC) added the new section titled “Al- of the previously separate diluent and drug lergenic Extracts as CSPs” based on evidence contents) container pairs of drug products that 27,000 immunotherapy injections, which for intravascular administration (e.g., ADD- ® ® ® were not prepared in ISO classified controlled Vantage , Mini Bag Plus , AddAVial , Add- ® ® environments by personnel gloved and garbed Ease , Duplex ) is to be applied as indicated 1 according to standards specified in the chapter by the manufacturer. However, the Joint for low- and medium-risk level CSPs, were not Commission™ does have facility standards for associated with any infections.6 USP Chapter medication preparation (see other regulatory <797> specifies suitably-preserved allergen requirements below). extracts as CSPs are not subject to the environmental, and beyond-use date storage require- Other Regulatory Requirements for ments for all CSP microbial contamination risk Facilities levels but only when all of eleven criteria listed in Chapter <797> are met. Non-preserved al- In addition to USP Chapter <797> standards lergen extract CSPs must comply with the ap- for air cleanliness, two regulatory organiza- propriate Chapter <797> CSP risk level require- tions have requirements for sterile preparation

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facilities. The Food and Drug Administra- and ISO Class 8 conditions for 0.5-micron and tion (FDA) requires pharmacists to use good larger particles under dynamic conditions for manufacturing practices,7 including a facility the ante-areas. The buffer area must be seg- of suitable size, construction, and location to regated from surrounding, unclassified spaces facilitate cleaning, maintenance, and proper to reduce the risk of contaminants being operations. Second, the Joint Commission blown, dragged, or otherwise introduced into on Accreditation of Healthcare Organizations the filtered unidirectional airflow environment, (Joint Commission™) standards for hospitals and this segregation must be continuously simply state8: monitored with a pressure gauge. For sterile compounding areas providing a physical sepa- Whenever medications are prepared, ration between buffer and ante areas through staff uses appropriate techniques to the use of walls, doors, and pass-throughs, avoid contamination during medication a minimum differential positive pressure of preparation, which include but are not 0.02- to 0.05-inch water column is required. limited to: For buffer areas not physically separated from l Using clean or sterile techniques the ante-areas, the principle of displacement airflow must be employed. This concept uti- l Maintaining clean, uncluttered, and lizes a low pressure differential, high airflow functionally separate areas for product principle. Using displacement airflow typically preparation to minimize the possibility of contamination requires an air velocity of 40 feet per minute or more from the buffer area across the line of l Using a laminar-airflow hood or other demarcation into the ante-area.1 The displace- Class 100 environment while preparing ment concept must not be used for high-risk any intravenous (IV) admixture in the compounding. pharmacy, any sterile product made from non-sterile ingredients, or any sterile PECs must be placed within a buffer area product that will not be used within 24 in such a manner as to avoid conditions that hours could adversely affect their operation. For example, strong air currents from opened doors, l Visually inspecting the integrity of the personnel traffic, or air streams from the HVAC medications systems can disrupt the unidirectional airflow in open-faced LAFWs.1 Dispensing adheres to law, regulation, licen- sure, and practice standards, including record HEPA filters should be located above the keeping.9 In preventing pediatric medication ceiling the air flowing in a unidirectional man- errors, the Joint Commission™ sets forth risk ner into the buffer area and ante-area. The reduction strategies, including, at a minimum, HEPA filter in the ceiling air supply should pediatric medications should be stored and be placed to avoid creating air currents inside prepared in areas separate from those where the laminar-airflow workbench. Pre-filters on adult medications are stored and prepared.10 the heating, ventilation, and air conditioning (HVAC) air blower should be changeable from outside the ante-area/buffer area.11 Buffer Area and Ante-area Air return grills should be located low on the walls. Low wall mounted air returns are Heating, Ventilation, and Air somewhat more difficult to install but are Conditioning (HVAC) much more efficient in removal of airborne particulate contamination. Low wall returns Under USP Chapter <797>, sterile compound- should be well distributed throughout the ing areas must provide a comfortable and room and ideally have adjustable louvers or well-lighted working environment, which dampers.12 typically includes a temperature of 20 °C. or cooler, to maintain comfortable conditions for compounding personnel to perform flaw- Surface Characteristics lessly when attired in the required aseptic USP Chapter <797> stipulates that the surfac- compounding garb. Buffer areas are designed es of ceilings, walls, floors, fixtures, shelving, to maintain at least ISO Class 7 conditions for counters, and cabinets in the buffer area must 0.5-micron particles under dynamic conditions be smooth, impervious, free from cracks and

265 Compounding Sterile Preparations crevices, and nonshedding, thereby promoting (see Chapter 4). Placement of devices (e.g., cleanability and minimizing spaces in which computers, printers) and objects (e.g., carts, microorganisms and other contaminants may cabinets) that are not essential to compound- accumulate. The surfaces must be resistant ing in buffer areas is dictated by their effect to damage by disinfectant agents. Junctures on the required environmental quality of air of ceilings to walls must be coved or caulked and surfaces, which must be verified by viable to avoid cracks and crevices where dirt can and nonviable air sampling. 1 Space must be accumulate.1 provided in or convenient to the ante-area for If ceilings consist of inlaid panels, the pan- storage of sterile garb (gowns, gloves, hair and els must be impregnated with a polymer to shoe covers, face masks and goggles) and for render them impervious and hydrophobic, and supplies that are needed for equipment (e.g., they must be caulked around each perimeter pre-filters for PECs, automatic compounder to seal them to the support frame. Walls may sets, labels, etc.). be constructed of flexible material (e.g., heavy With regard to non-sterile chemicals used in gauge polymer) panels locked together and high-risk compounding, USP Chapter <1075>: sealed, or of epoxy-coated gypsum board. Pref- Good compounding practices says that bulk erably, floors are overlaid with wide sheet vinyl drugs and other chemicals or materials used flooring with heat-welded seams and coving to in the compounding of drugs must be stored the side-wall. Dust-collecting overhangs, such as directed by the manufacturer, or according as ceiling utility pipes, and ledges, such as to USP monograph requirements, in a clean, windowsills, should be avoided. The exterior dry area, under appropriate temperature con- lens surface of ceiling lighting fixtures should ditions (controlled room temperature, refrig- be smooth, mounted flush, and sealed. Any erator or freezer).13 Presterilization procedures other penetrations through the ceiling or walls for high risk level CSPs, such as weighing and must be sealed.1 mixing, must be completed in no worse than The buffer area must not contain sources an ISO Class 8 environment (e.g. in a separate of water (e.g. sinks, eye washes) or floor room with a controlled air environment). All drains. Work surfaces must be constructed of high risk level CSP solutions subjected to ter- smooth, impervious materials, such as stain- minal sterilization are pre-filtered by passing less steel or molded plastic, so that they are through a filter with a nominal pore size not easily cleaned and disinfected. Storage shelv- larger than 1.2 microns preceding or during ing, counters, and cabinets must be smooth, filling into their final containers to remove impervious, free from cracks and crevices, particulate matter. All nonsterile measuring, nonshedding, cleanable, and disinfectable. mixing, and purifying devices are rinsed thor- Their number, design, and manner of instal- oughly with sterile, pyrogen-free water, and lation must promote effective cleaning and then thoroughly drained or dried immediately 1 disinfection.1 before use for high-risk compounding.

Placement of Equipment and Supplies Environmental Sampling and Testing USP Chapter <797> explains that the quality USP Chapter <797> specifies that the environ- of the environmental air improves with move- mental sampling and testing program must ment from the outer boundary of the ante-area demonstrate that PECs (LAFWs, BSCs, CAIs, to the direct compounding area (DCA) within and CACIs) are maintaining an environment PECs. Placement of devices in ante-areas and in the compounding area that consistently buffer areas is dictated by their effect on the ensures acceptably low viable and nonviable designated environmental quality of atmo- particle levels. The compounding area includes spheres and surfaces, which must be verified the ISO Class 5 PEC, the buffer areas, and/ by viable (microbial) and non-viable (particu- or segregated compounding areas and the 1 late) air sampling.1 See Chapter 24. ante-areas. It is the responsibility of every sterile com- Environmental sampling must occur as pounding supervisor to ensure that each PEC part a comprehensive quality management environment for exposure of critical sites and program and must occur minimally under any sterilization by filtration is properly located, of the following conditions: 1) as part of the operated, maintained, monitored, and verified commissioning and certification of new facili-

266 Chapter 21 Secondary Engineering Controls ties and equipment; 2) following any servicing commodate planned activities, along with of facilities and equipment; 3) as part of the a timeline to show when facility needs will re-certification of facilities and equipment (i.e., occur. The pharmacy department should every six months); 4) in response to identified have its own master facilities plan, keyed problems with end products or staff technique; to its strategic plan, and congruent with or 5) in response to issues with CSPs, observed the hospital’s strategic plan. compounding personnel work practices, or 2. Analysis of existing facility includes as- patient-related infections (where the CSP is built plans, space inventory room by being considered as a potential source of the room, equipment list showing age and re- infection). 1 Therefore, suitable space must be placement value, site surveys, assessment provided for sampling swabs, agar plates, in- of structural, mechanical, and electrical cubator, etc. See Chapter 24 on environmental systems, code conformity, and traffic pat- quality and control. terns. 3. Functional program includes block dia- grams that show department components, Cleaning and Disinfecting flow and traffic relationships, phases in USP Chapter <797> states, “Environmental development, new versus renovated space, contact is a major source of microbial con- gross cost estimate, and a statement of tamination of CSPs. Consequently, scrupu- assumptions and priorities. lous attention to cleaning and disinfecting 4. Architectural schematic plans include the sterile compounding areas is required to alternatives, showing layout and design minimize this as a source of CSP contamina- of departments and relationships plus tion.”1 Therefore, appropriate space must be workflow of staff, materials, and patients provided for cleaning supplies, sterile 70% iso- (includes a brief description of fixtures, propyl alcohol and other disinfectants, trash mechanical and electrical systems, and a containers for all waste streams involved, etc. cost estimate). See Chapters 15 and 23. 5. Architectural design adds all other architectural details, including the last review by the users. Planning the Sterile Preparation 6. Construction contract includes final draw- Facility ings for regulatory approval and bidding plus the final cost estimate. Allen et al. presented a detailed planning 7. Construction includes demolition, con- process for designing and evaluating a sterile struction, equipment ordering, and in- compounding facility.14 The authors used a spection. strategic functional planning approach. This allowed them to meet hospital goals for effi- 8. Commissioning for occupancy includes ciency, functionality and a planned future re- installation of equipment, orientation of location of the sterile compounding center. The staff, moving, post-occupancy evaluation functional program development took them (i.e., validation, certifications), and follow- up. through: work flow, work load, equipment, storage, arrangement of work areas, space requirements, floor plan and evaluation of the Strategic Master Facilities Plan facility. They were able to improve pharmacist The first step, developing a master facilities efficiency by 42% and technician efficiency by plan, involves identifying and justifying the 29% within a modest-sized facility that met need for a new facility. ASHP sterile compounding facility standards extant in 1995. The cost of the equipment and fixtures was $70,000–$75,000.15 Identifying Need The functional planning approach includes Before updated facilities can be justified, the eight key steps that can be used for large or pharmacy department must determine its small construction projects16: specific need based on its patient population. Three questions can be asked to determine 1. Strategic master facilities plan sets forth this need. the implications of the hospital strategic plan in terms of the facilities needed to ac- What guidelines apply to the patient popula-

267 Compounding Sterile Preparations tion? Some state pharmacy laws or regulations The primary functions of a well-designed buf- require that USP Chapter <797> standards be fer area are to remove internally generated followed. See Chapter 1. contamination and to prevent it from adversely What are the highest level sterile prepara- affecting the direct compounding area (i.e., 17 tions that will be compounded? Unless there is inside workbench environment). no chance that high-risk preparations will ever Q. If pharmacy-prepared admixtures at this be compounded, following the USP Chapter hospital have never been implicated in noso- <797> standards for high-risk compounding comial infections, why should these facilities is the most conservative approach. be upgraded? A. Pharmacy-prepared sterile Will hazardous drugs be compounded? preparations are not commonly implicated Compounding hazardous drugs will require because few institutions thoroughly investi- additional primary (i.e., BSC or CACI) and gate the causes of nosocomial infections. In secondary engineering (i.e., segregated nega- fact, pharmacy-compounded sterile prepara- tive pressure buffer room) controls. tions have often been traced back to poor pharmacy aseptic compounding technique (see Chapter 1). Justifying Need Q. Isn’t good aseptic technique more impor- Pharmacy directors frequently face resistance tant than a buffer area in preventing microbial (both from administrators and pharmacy contamination? A. One study showed that personnel) when justifying the need to im- when sterile preparations are contaminated, prove their facilities. Some commonly asked touch contamination (as evidenced by skin questions and their corresponding answers bacteria) is much more common that con- follow. tamination from the environment.18 However, Q. If admixtures are made within a laminar- well-maintained buffer areas provide a clean, airflow workbench, why does its location mat- comfortable, correctly-arranged environment ter? A. Laminar-airflow workbenches do not for primary engineering controls optimally to eliminate 100% of airborne particles. These create an aseptic direct compounding area workbenches have high-efficiency particu- where critical sites can be exposed. Requiring late air (HEPA) filters that remove 99.97% of proper personnel garbing and hand cleansing particles over 0.3 microns when operating prior to entering a buffer area also minimizes properly.17 A significant increase in airborne unnecessary traffic in the area of compound- contamination outside the workbench sig- ing. nificantly increases contamination within Q. Since building an ante-area and buf- the workbench. Workbenches cannot prevent fer area will be expensive, why not return microbial contamination introduced by poor the responsibility for admixture preparation aseptic technique downstream from the HEPA to nurses? A. True, in admixtures prepared filter (e.g., from air currents pushing room air just prior to administration, accidentally in- into the workbench). troduced microbes have less time to grow to Q. If the workbench is already in a separate pathological levels. But one study showed that room, do you really need a buffer area and 21% of the admixtures were made incorrectly ante-area? A. A separate room minimizes (as to ingredients, dosage, unordered admix- unnecessary traffic near the workbench but ture, or incompatibility) on nursing units.19 not the contamination already in a room. For Moreover, nurses are less well trained to make example17: admixtures today than when this study was published. Furthermore, since many sterile l A person sitting motionless generates preparations are used for 24 hours or more about 100,000 particles/cu ft/min. (e.g., TPNs and patient-controlled analgesia l A person sitting down or standing up syringes), microbes can easily grow to patho- generates about 2,500,000 particles/cu logic levels at room or body temperatures. USP ft/min. Chapter <797> does exempt manufacturer’s l A person walking generates about bag and vial systems from all chapter stan- 10,000,000 particles/cu ft/min. dards and this exemption is used in many hospitals for critical patient needs.20 l An open, non-airlocked door can add bil- lions of particles/cu ft/min. Q. Finally, what agency is going to force our institution to adopt USP Chapter <797>

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sterile compounding facility standards? A. The Allen et al. found that their “open” sterile state board of pharmacy is the most powerful compounding center required 727 square feet agency inspecting pharmacies. At least nine in floor space including a separate hazardous states require partial or full compliance with drug compounding area for a teaching hospital USP Chapter <797> and most state boards with an average of 441 occupied beds and 800 of pharmacy are reviewing the new Chapter IV admixtures per day.14 <797> to decide whether or how to enforce For hand washing, a sink with hot and this chapter. The Joint Commission™ requires cold running water should be in the ante- accredited health care institutions to review area but not the buffer area. Ventilation and and decide how to use Chapter <797>. Courts room temperature control should be in ac- of law will use Chapter <797> as the “com- cordance with USP Chapter <797> standards munity standard” for sterile compounding. (See above discussion). In any enclosed space See Chapter 1. with heat-producing equipment, the air con- Douglas recommends that pharmacy direc- ditioning must keep personnel comfortable tors write a 5 to 10 page white paper to justify in cleanroom garb. Lighting should ensure physical plant changes to bring pharmacy into that personnel can read packages easily (e.g., conformance with USP Chapter <797>.21 To syringe gauges and drug labels) and visualize be effective, the white paper should address: contaminants (e.g., glass fragments in ampuls regulatory standards, patient safety improve- and rubber cores in vials). 24 ment and reduced potential for litigation, fis- cal impact as to personnel efficiency, capital Room Separation expenditures and return on investment, com- petitive advantage in the health care market, An ISO Class 7 buffer area and ISO Class 8 alternative solutions and why they were ruled ante-area are mandatory. Seventeen percent out.22 Determine the stakeholders who will of hospital pharmacies compound high-risk 25 read the white paper. Use language that is preparations. Any hospital that compounds, familiar to the stakeholders, e.g., patient and or has the potential to compound, high-risk employee safety, finances, regulations. Use preparations must have the ante-area sepa- tables to present more detailed information, rated from the buffer area by a solid wall with 1 like alternatives considered—pros and cons, a door that closes. See section on “open” and effects on staff efficiency, building, equipment “closed” sterile compounding facilities below. and supply costs.

Existing Facility Once the need has been justified, the next Table 21-4. step is to determine whether a current sterile Space Allocation for Sterile compounding area can be updated, whether a Compounding Areas* new compounding area is needed, or whether a new type of environmental control (e.g., Number of Staffed Beds Square Footage compounding isolator) should be employed. (mean ± S.E.) Room size and environment (e.g., temperature, < 50 (n = 40) 83 + 15 humidity and lighting) as well as cleanliness 50–99 (n = 65) 208 + 21 levels are important considerations. 100–199 (n = 57) 294 + 37 Size and Environment 200–299 (n = 52) 441 + 52 A survey conducted in 2006 of 341 U.S. hos- 300–399 (n = 61) 661 + 108 pitals showed an average of 310 square feet of > 400 (n = 66) 976 + 280 floor space allocated for compounding sterile All hospitals (n = 341) 310 + 26 preparations (see Table 21-4). Considering that a minority of hospitals had upgraded their sterile compounding facilities in line with USP *Source: Pederson CA, Schneider PJ, Schec- Chapter <797>, 81.3% of respondents to this kelhoff DJ. ASHP national survey of pharmacy survey indicated that their space allocations practice settings: Monitoring and patient educa- were not adequate for sterile compounding.23 tion-2006. Am J Health-Syst Pharm. 2007;64:507–20.

269 Compounding Sterile Preparations Functional Program Ante-Areas and Buffer Areas The functional program is a large volume of A high-cleanliness ante-area reduces the num- detailed performance specifications to provide ber of particles in the buffer area. Appropriate the designer or architect with details for all activities for the anteroom include but are not sterile compounding and related activities, limited to hand washing, gowning and glov- work flows, work loads, numbers of personnel ing, removal of packaging, and cleaning and to be accommodated, fixtures and equipment, disinfecting of hard-surface containers and storage needs, transportation and commu- supplies before they are placed in the buffer 1 nications, services, utilities environmental area. See Chapter 15. controls, security considerations, etc.16 The Figure 21-1, from proposed USP Chapter key point in functional programming is to <797>, shows the important parts and spatial identify every specific function along with relationship of a buffer area to an ante area the required methods and systems to be per- suitable for low and medium risk sterile com- formed in the facility. After existing facilities pounding.26 This configuration is sometimes have been analyzed, one primary decision has referred to as an “open” cleanroom. to be made: Should a custom-built ante-area/ Figure 21-2 represents USP’s schematic buffer area be planned or should a modular floor plan for a high-risk sterile compounding ante-area/buffer area be purchased? Or can facility.26 This configuration is sometimes re- an existing room be remodeled or procedures ferred to as a “closed” cleanroom. Access to the be implemented to create a facility that meets buffer room should be via the anteroom door ante-area/buffer area air quality standards? for personnel and via an airlock pass through

Figure 21-1. Schematic drawing of an “open” ante-area and buffer-area (not to scale).

270 Chapter 21 Secondary Engineering Controls for most supplies. As supplies are moved from 6. Shipping costs for aluminum and vinyl the anteroom into the buffer room and then components are less costly than steel and into the PEC, a series of cleaning steps should unassembled components. be followed (see Chapter 15). 7. Installation costs are less because the vendor will do most of the installation, Modular Ante-Area/Buffer Areas with the exception of electrical, water and HVAC hook-ups. Modular ante-area/buffer areas (as opposed to custom built) have several advantages: For low-volume operations, soft-wall ante- 1. Modular ante-area/buffer areas can be area/buffer areas are available at a lower cost customized to specific needs of the insti- than modular hard-wall installations. The tution. pharmacy at Memorial Hospital in Carthage, IL, had a soft-wall ante-area/buffer area 2. No sanding, spackling, or painting of walls (Figure 21-3) installed for under $20,000 (in are necessary, leaving a cleaner environ- 1995 dollars) that satisfied a JCAHO home ment. care survey. Some facts about this ante-area/ 3. Modularity allows future change if chang- buffer area include28: es are anticipated in aseptic processes or volume, or relocation to another site. l Setup of tubular frame and vinyl plastic panels took 10-12 hours for two company 4. Modular ante-area/buffer areas cost less personnel. and are more rapidly installed, reducing construction time by 20% to 40%.27 l Dimensions are 8 feet by 16 feet, with an 8-feet ceiling height. 5. Modular systems use standard components that are often available from differ- l Three “movable” walls are connected to ent suppliers. one rigid wall. The rigid wall contains elec-

Figure 21-2. Schematic drawing of a “closed” anteroom and buffer room (not to scale).

271 Compounding Sterile Preparations

trical and plumbing fixtures. It is made of aluminum stud supporting fire-rated dry wall and is painted with epoxy paint to provide durability and prevent particle shedding. l Soft walls are made of 16-mil, replaceable, clear vinyl panels attached to a strong tubular frame. l The ante-area/buffer area door is the same vinyl-on-tubular frame construction. l The pass-through chamber is 16 inches by 16 inches. l Two 2-feet by 4-feet HEPA filters are suspended in the ante-area/buffer area ceiling. Air from the pharmacy proper is blown through two standard fiberglass filters before passing through the HEPA Figure 21-3. Pharmacist in a soft-wall cleanroom filters into the ante-area/buffer area. at Memorial Hospital, a 67-bed hospital in Carthage, IL. l Louvered dampers in the door and below the pass-through chamber permit airflow out of the positive-pressure room. They can be closed if power is lost to the the chance of error due to interruptions, they blower. placed no phone in their ante-area/buffer area l Ceiling tiles are vinyl-coated gypsum pan- and included only a foot-activated intercom els. for outside communications. l Vinyl panels are easy to clean with de- Samuelson and Clark described the plan- tergent and water and can be replaced ning for an ISO Class 7 buffer area with an inexpensively if torn. ISO Class 8 anteroom at the University of Il- linois Hospital.31 They decided to convert an l A “hands free” faucet and hand dryer are existing 32-feet by 22-feet sterile preparations just outside the ante-area/buffer area. room 40% into a buffer area and 60% into l The airborne particle count in the clean- an ante-area by constructing a wall across room is about 65 of 0.5 microns or larger it. The large anteroom was needed for stock per cubic foot, easily qualifying the envi- storage and reference materials. A larger pass- ronment as ISO Class 7 or even ISO Class through window was used for supplies going 5. Particle counts inside the laminar- into the buffer area, and the smaller window, airflow workbench average 5–10 of 0.5 for completed preparations going back to the microns or larger. ante-area where a pharmacist checks them. The glass panel around the windows preserved Compared to soft-wall ante-area/buffer areas, a sense of openness and allows the pharmacist hard-wall modular ante-area/buffer areas to monitor activities in the ante-area/buffer with rigid panels attached to a frame offer area. Since the existing walls and floor were more stability and better seals to maintain seamless, they could be sealed with a poly- ante-area/buffer area integrity.29 Hard-wall mer coating. However, ventilation had to be ante-area/buffer areas are also easier to keep changed to incorporate HEPA filtration of the clean and are more durable. air supply in conjunction with a new two-inch ceiling grid system. Remodeling Existing Space In a 321-bed community hospital, Schu- Kuster and Snyder gave reasons for renovat- mock et al. described their remodeling project ing their pharmacy to create an ISO Class 7 to create an ISO Class 7 buffer room.32 The ante-area/buffer area.30 They prepared vari- authors planned and implemented a 361 ous sterile preparations, including high-risk square foot facility that paid for itself ($39,486 preparations such as glycerin and phenol in 1996 dollars) in less than two years via injection and sterile talc injection. To lessen the batch production of selected unit-of-use 272 Chapter 21 Secondary Engineering Controls

syringes not available commercially, i.e., sav- In lower volume facilities or for pharmacy ings were from reduced waste and extended night shift or satellite operations, pharmacists expiration dating. might consider installing a compounding isolator in existing space. This is an option for Minimal Facility Change low and medium risk compounding only. The CAI or CACI must meet USP Chapter <797> Pharmacy managers find it tempting to convert conditions to be considered for use outside an a traditional sterile compounding space to an ISO Class 7 buffer room, i.e. complete isola- ante-area, buffer area space. This is difficult tion from the surrounding room, minimum for several reasons. Adding enough ante-area air particle counts in the direct compound- usually takes more space; there may not be ing area and at the transfer door when the enough overhead space for adding HEPA filters surrounding room.1 See Chapter 4. If a CACI and their air grills; low wall air returns can that meets the Chapter <797> requirements be a problem; adding plumbing for a sink in is used for compounding hazardous drugs the ante-area is tough if the pharmacy is on outside an ISO 7 buffer area, it must be in a the bottom floor; exhausting a BSC or CACI to segregated compounding room that maintains the outside for compounding hazardous drugs a minimum negative pressure of 0.01-inch may be difficult and so on. Remodeling existing water column and have a minimum of 12 air space also poses the difficulty of finding swing changes per hour.1 space for sterile compounding during weeks A non-ISO 7 alternative for low-risk com- or months of construction. pounding for sterile preparations with 12- As mentioned, the USP Sterile Compound- hour or less beyond-use dates is to create a ing Committee believes that it is relatively segregated compounding area. Placement of easy to convert an ISO Class 8 buffer room devices (e.g., computers, printers) and objects to an ISO Class 7 buffer room. However, the (e.g., carts, cabinets) that are not essential to American Society for Healthcare Engineering compounding in the segregated area should be (ASHE) states that converting ISO 8 to ISO 7 limited, based on their effect on air quality in and requiring HEPA air filtration will signifi- the ISO Class 5 primary engineering control.1 cantly increase the costs to design, construct, and operate the ventilation component of pharmacy buffer rooms, particularly if the Architectural Schematic Plan design is to retrofit an existing ventilation Pharmacists should prepare plans with a hos- system. They say increasing the air quality pital designer or architect in line with the de- from ISO Class 8 to ISO 7 will require sub- tailed specifications in the functional program. stantially greater air flow and cost (see Table For the hospital architect unfamiliar with 21-5.) Existing supply fans to ceiling air grills ante-area/buffer area design, ISO Standard may be insufficient to overcome the resistance 14644-4 specifies the requirements for the of HEPA filters, in which case hospitals must design and construction of ante-area/buffer install in-line booster fans to maintain a posi- area facilities.34 This standard is intended for tive pressure of the buffer area relative to the use by purchasers, suppliers and designers ante-area.33 of ante-area/buffer area installations and

Table 21-5. Cost of Converting an ISO Class 8 Buffer Room to an ISO Class 7 Buffer Room*

ISO Class Ceiling Covered by Air Grills Approximate Cost of Ceiling Air Grills 8 5%–15% $50 per square foot 7 15%–20% $200–$250 per square foot

*Source: Woodin D. Deputy Executive Director, American Society for Healthcare Engineering. Comments on summary of proposed revisions to <797>. http://www.ashe.org/ashe/codes/advisories/pdfs/comment090905_ usp797rev3.pdf Accessed February 4, 2008. 273 Compounding Sterile Preparations provides a checklist of important parameters Together the pharmacist and designer/ar- of performance. Construction guidance is pro- chitect find optimal arrangements for work vided, including requirements for qualification areas, find the best location, calculate space and start-up activities. and develop trial schematics. The architect’s The pharmacist has the following roles in role is to translate all of this into architectural functional planning16: plans, i.e., determining how much square footage is needed, designing the layout of l Derive pharmacy goals and objectives as the space, specifying construction materi- to sterile compounding. als, developing project budgets, producing l Identify functions to be performed in the blue prints and issuing change orders. The ante-area and buffer area. architect may be on the hospital staff, may be hired by the construction project or may l Determine workflow in the ante-area and be supplied by the construction company. buffer area. Some hospital architects will need to review l Determine the physical environment recommended practices in ante-area/buffer needed. area design.35,36 l Decide how to handle workload during the renovation process. Construction Contract l Specify requirements for the ante-area and buffer area: Preparing the Request for Information (RFI) l Workload (e.g., average and maximum Before asking a vendor to bid on building daily numbers of parenteral nutrition an ante-area/buffer area, evaluate potential solutions, batches of syringes, che- vendors by asking for information about their motherapy compounding, peritoneal abilities and resources; solicit financials or dialysates, stat admixtures). Dun and Bradstreet reports and ask for a list- l Equipment types and numbers. Will ing of recently completed projects in facilities biological safety cabinets or isolators like yours. Call for references or visit some of be exhausted to the outside (they these facilities. Ask the vendor to submit a should be)? set of design plans for a similar project and l Storage requirements for supplies and resumes for the proposed project team. Select finished preparations. three to five vendors to whom you will submit l Personnel types and numbers. a request for proposal. l Materials handling. Handling the Request for Proposal (RFP) l Communication systems (e.g., intercom, email, telephones, overhead Together, the pharmacist and hospital engi- paging). neer or architect should prepare the RFP and select the potential vendors most likely to serve l Services expected from other depart- the facility’s needs. The request for proposal ments (e.g., IV solution deliveries, can follow these guidelines37: housekeeping). l Security (e.g., locked doors, access 1. Supply potential vendors with pertinent control systems, video cameras). information to meet the requirements but not so detailed as to stifle their creativity. l Utilities (e.g., lighting, electrical out- lets, plumbing, computer lines.) 2. Provide a general overview of the facility and its requirements, e.g., the type of work l Environmental quality control (i.e., to be done, hours of operation. ISO Class 5 or 7 or 8). 3. Present the scope of work to be provided l Housekeeping and cleaning rou- by the vendor, i.e., design, construction, tines. electrical, heating, ventilation, and air l Environmental sampling routines conditioning (HVAC), institutional or ven- (e.g., laminar air-flow workbench test- dor-supplied connections for electrical, ing, air and surface microbial counts, ventilation, gases, etc. James T. Wagner air particulate counts). (author of Chapter 4) recommends that Type C HEPA filters be used in pharmacy ante-area/buffer area air supplies.38 274 Chapter 21 Secondary Engineering Controls

4. Ask for a proposed project schedule, floor saving setback controls if the ante-area/ plan, ceiling plan, elevations, equipment buffer area is not operating 24 hours per location plan, and air balance schematic, day, 7 days per week. What lighting levels as well as details and catalog cuts of are needed (in foot-candles) at 30 inches preparations and materials used as the from the floor in the buffer area (e.g., 140) basis of the design. Ask for heat load cal- and ante-area (e.g., 100)? Requirements culations and rough power requirements. for a sprinkler system in the ante-area/ Must construction and service personnel buffer area are dependent on the oc- be union members? Use all this informa- cupancy code and use, as well as local tion to compare proposals and for inter- building codes. Sprinkler heads should views with potential vendors. be flush with the ceiling. How far away is 5. Show taxable status of the project so the tie-in point for sprinkler water sup- the vendor knows what to include or not ply? Will the water supply be shut down include as regards permits, stamps, and or will it need to operate during the tie-in fees. process? What are the insurance policy requirements for the sprinkler system? 6. Specify that your compounding area is to Will smoke or fire alarms be needed in the be an ISO 7 buffer area with an ISO Class ante-area/buffer area? Are hot and cold 8 ante-area for airborne particles, tempera- water available for the ante-area? Can a ture (i.e., 20 ºC.), humidity (e.g., 45%–60% sink drain be installed in the ante-area? relative humidity), air pressure gradients Who will remove waste material? How will between the buffer area and ante-area hazardous and nonhazardous waste be and the ante-area and surrounding space handled? See Chapter 15. and air exchanges per hour (i.e., 30 air exchanges per hour in the buffer area). HVAC 9. Require the vendor to do an onsite inspec- control is the biggest issue in design, be- tion of your facility before developing a cause garb, workbenches and refrigerators quotation. increase warmth for people in ante-area/ 10. Ask for the vendor to train your personnel buffer areas. The number of people in the who will use and maintain the ante-area/ compounding area will also add heat and buffer area, e.g., engineers, housekeeping, moisture to the environment. pharmacy personnel. 7. Supply a schematic floor plan or bubble 11. Ask for a price breakdown, per building diagram, equipment list, material path- trade, allowing you to evaluate where ways, ceiling height (slab to slab), cur- there are differences in proposals. Is pay- rent floor construction, and any seismic ment or performance bonding required? or structural issues so the vendor can accurately assess construction require- 12. Develop an evaluation matrix to compare ments. What cleaning agents will be used proposals. Interview the two or three ven- on ceilings, walls, and floors? Are windows dors who look most promising, based on or viewing panels required? If so, where criteria that you have set for your insti- should they be? Are pass-through cham- tution. Discuss architecture, mechanical bers required? If so, where and what size systems, heat load calculations including should they be in the ante-area and buf- wall insulation, and electrical and lighting fer area? Where are doors to be located systems. in the ante-area and buffer area? What 13. Arrange to have the completed ante-area/ type of door (e.g., flexible vertical slats, buffer area evaluated by an independent swing, or sliding) should be installed? Do company based on your RFP performance perimeter walls require fire rating? If so, criteria. Determine who will pay for the identify rating in hours for the ante-area final evaluation. and buffer area. Are temperature record- ing and monitoring devices to be built in 14. Negotiate the schedule that protects within the ante-area and buffer area? both parties from unforeseen delays and costs. 8. Present a utility plan. Will additional electrical power be needed? Hospital engineer- 15. Ask what you, as the owner, will have to ing personnel can usually bring the power do to operate the ante-area/buffer area source to a single point of connection at after the vendor’s work is complete. a lower cost than having the ante-area/ 16. Finally, have the institution’s pharmacist, buffer area vendor arrange the power engineer, administrator, and lawyer select source. You may wish to have energy- the best ante-area/buffer area vendor.

275 Compounding Sterile Preparations

Lawyers for the vendor and institution will levels), surface conditions, environmental re- finalize the contract for the administra- quirements (temperature and humidity), and tor’s approval. working conditions (e.g., space, sound, and lighting levels) are as specified in the original Construction bidding process. These requirements must be satisfied be- Whether planning custom-built or modular fore any equipment or supplies are moved construction, everyone involved in construct- into the ante-area or buffer area. The vendor ing an ante-area/buffer area should under- should supply an operation and maintenance stand that this is no ordinary building project. manual that will help identify problems and The microbial contamination potential of all possible solutions. This manual should also activities should be reviewed before they are provide scheduling for maintenance and parts begun. Institutional staff should monitor replacement. vendor personnel to ensure that they follow Furthermore, the institution’s facilities proper techniques so as not to build con- management personnel must check that all tamination into the ante-area/buffer area or policies regarding electrical fixtures, heating, its surroundings. Issues should be resolved ventilation, etc., have been met. An agreement with the vendor onsite, not after construction must be reached with the vendor to rectify is complete. deficiencies before the contract can be con- Materials for walls, floors, and ceilings sidered satisfied. should never be stored outdoors. Packaging Ante-area/buffer area vendor should be materials (usually doubled) cannot be torn required to pay to have independent facility or removed until the ante-area/buffer area certification and validation. This may involve vendor is ready for installation. A general wipe three phases of certification40: down of building materials with clean wipes is recommended both before and after installa- l Phase 1—Installation Qualification. As- 39 tion. After any cutting or drilling operation, built testing or construction approval. the resealing should be done as soon as pos- This proves the environment was correctly sible to prevent oxidation or deep contamina- installed and that it meets functional de- tion of building materials. sign specifications. Once the floor is laid, construction work- l Phase 2—Operational Qualification. At- ers should wear gowns and shoe covers to rest testing or functional approval. This reduce contamination and prevent damage to testing is performed with all the equip- the floor. No eating, smoking, chewing, etc., ment present and operating but without should be allowed in the area. All spills, fil- personnel present. It is necessary to see ings, etc., should be cleaned up immediately. that primary and secondary engineering After walls and ceilings are in place (even controls work properly together. before the air supply is turned on), the area l Phase 3—Performance Qualification. Also should be restricted to authorized personnel. called dynamic operational testing, it is a Finally, once the air supply is on, construction series of tests or certifications that deter- workers should be gowned like the operators mine whether the completed installation will be.39 achieves the functional standards during routine operations. USP Chapter <797> requires that secondary engineering Commissioning for Occupancy controls meet standards during dynamic Final steps are inspecting and approving the operations like those in the CETA Certi- new facility, installing and evaluating equip- fication Guide for Sterile Compounding Facilities.41 The Controlled Environment ment, moving supplies, assessing workflow, Testing Association (CETA) guide covers and following up on needed changes (which tests for airflow testing including smoke are inevitable). Use of a qualified independent patterns, room pressurization, airflow dis- testing agency is recommended to assure un- placement, HEPA filter installation leaks, biased test results. air particle counts and optional tests for The sterile compounding supervisor must lighting and noise levels, temperature and be sure that air quality (balance and particle humidity controls.

276 Chapter 21 Secondary Engineering Controls Facility Maintenance Certification Guide for Sterile Compounding Facilities be performed by a qualified indi- Clearly, planning, building, and implement- vidual no less often than every six months and ing an ante-area/buffer area is a detailed whenever a secondary engineering control is process. All that preparation, however, must relocated or altered or major service to the fa- be preserved with proper maintenance. Pre- cility is performed.41 This applies to segregated ventive maintenance of ante-area/buffer area compounding areas as well as ante-area/buf- pre-filters, HEPA filters, and ducts should be fer area sterile compounding facilities.1 See arranged with appropriate maintenance per- Chapter 24. sonnel or a service vendor. Similarly, lighting should be checked periodically and/or bulbs should be changed. Environmental Sampling and Testing In addition to recertification, USP Chapter Cleaning and Disinfecting (see also <797> stipulates that routine monitoring and testing of secondary engineering controls: air Chapter 23) microbial and surface testing, air pressure Each day, work surfaces near the primary differential monitoring in “closed” ante-area/ engineering control(s) (e.g., counter tops and buffer areas and differential airflow velocity in carts) should be wiped clean with a freshly “open” ante-area/buffer areas, temperature prepared mild detergent solution followed by and humidity controls.1 See Chapter 24. an approved disinfectant. Sufficient time must be allowed for the agent to exert its antimi- Corrective Actions crobial effect. Furthermore, storage shelving should be emptied of all supplies, cleaned, Whenever monitoring and testing fall outside and disinfected at least monthly. Re-cleaning acceptable ranges, corrective actions are should be performed if spillage or other events required. If colony-forming unit counts are indicate the need.1 too high in microbial air or surface testing, a When no aseptic operations are in progress, review of personnel garbing, traffic patterns, floors should be mopped once daily by trained cleaning and disinfecting, etc., is required. and supervised personnel. Floors should not If air pressure differential or airflow velocity be waxed because dried, worn wax adds to monitoring, temperature or humidity are out- airborne particulates.42 All cleaning and sani- side the normal range, the heating, ventilation, tizing agents should be approved, with careful and air conditioning system must be inspected consideration of compatibilities, effectiveness, by a qualified engineer and corrections must and inappropriate or toxic residues. In addi- be made. See Chapters 24 and 27. tion, all cleaning tools (e.g., wipers, sponges, and mops) should be nonshedding and used only in the buffer area (first) and ante-area. Summary Most wipers should be discarded after one Facilities used for sterile compounding play an use. If cleaning tools are reused, their cleanli- integral role in guaranteeing sterility, as does ness should be maintained by thorough rinsing proper garbing, hand hygiene, and aseptic and sanitizing and by storage in a clean envi- technique. Therefore, pharmacy departments ronment. Ceilings and walls should be cleaned should assess their current facilities and, monthly with a mild detergent solution followed if needed, upgrade or replace them. Once by an approved sanitizing agent.1 facilities have been brought up to USP Chap- Trash should be collected in suitable plas- ter <797> standards, a proper maintenance tic bags and removed with minimal agitation. program for the ante-area/buffer area must Routine monitoring is used to control the qual- be followed. ity of the air and surfaces in the ante-area/ buffer area. References Re-Certification 1. U.S. Pharmacopeial Convention. Chapter USP Chapter <797> requires that recertifica- <797> Pharmaceutical Compounding: tion procedures such as those in the CETA Sterile Preparations. http://www.usp.

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