Requirements

Medical Air Solutions, LLC. attended and participated in the USP Webinars (Web Seminar) held on June 6, 2007, February 21, 2008 and May 15, 2008. The Webinars were hosted by the United States Pharmacopeia (USP) to provide information and discussion on the final USP General Chapter <797> for clarification of various sections of the chapter. This included information, clarification and discussion on the final release that occurred on December 3, 2007.

There have been some significant changes from what was written in the previously proposed revision documents. Below is the URL to the USP web site’s FAQ page answering many “frequently asked questions” (FAQ). This is currently being revised again (as of August 29, 2011)

General Chapter <797> is the standard for the Compounding of Sterile Preparations (CSP). Medical Air Solutions, LLC. attended and participated in the USP Webinars (Web Seminar) held on June 6, 2007 and February 21, 2008. Both Webinars were hosted by the United States Pharmacopeia (USP) to provide information and discussion on the final USP General Chapter <797>.

The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) may be surveying this area for compliance with USP <797> but will not be issuing violations according to JCAHO’s Survey Director.

The U. S. Food and Drug Administration (FDA) has deemed USP <797> as a “Standard of Care” and will expect state Boards of Pharmacy to enforce compliance. To quote the USP June, 2006, USP <797> Webinar Guidebook:

“Thus, while the FDA generally defers to the states to regulate the practice of pharmacy and other health professions, it takes a keen interest in the quality and safety of the compounded preparations that reach patients. The FDA will act with states in investigating allegations of poor quality compounded drugs, but is willing and able under the FFDCA [Federal Food, Drug and Cosmetic Act] to act on its own initiative. The FDA intends to continue to work with states, but if a state is unwilling or unable to join the Agency’s efforts, the FDA may choose to act unilaterally to protect the public health from compounded drugs that pose unreasonable risks.”

Some members of the USP <797> committee feel that enforcing the USP <797> standard will fall to the individual state Boards of Pharmacy and that the FDA will rely on them only. With regard to the paragraph above, MAS feels the FDA may take a more active stance in having all locations that perform CSP meet this standard.

Some states and local governments may require an architect and/or engineer to approve any pharmacy renovation. They may also require more stringent measures be taken to ensure the safe compounding of sterile preparations.

Some of the items presented here will not necessarily be associated with the CSP environment or the engineering design. Much of the explanations for the risk types and descriptions of the various elements of USP <797> have changed which is why we strongly suggest you download the standard if available.

We are providing the entire list of definitions that is found in the December 3, 2007, standard. We have added some text to the definitions based on information received during the February 21, 2008, Webinar and from the FAQ posted on the USP web site in late 2009.

Air Change per Hour (ACPH or ACH) — The volume of air equal to the volume of a room/area that is mechanically supplied to or exhausted from that room/area.

Anteroom/Area (or Anteroom/Area) — An ISO Class 8 (see Table 1) or better area where personnel hand hygiene and garbing procedures, staging of components, order entry, CSP labeling, and other high-particulate generating activities are performed. It is also a transition area (airlock) that (1) provides assurance that pressure relationships are constantly maintained so that air flows from clean to dirty areas and (2) reduces the need for the heating, ventilating, and air-conditioning (HVAC) control system to respond to large disturbances.

Aseptic Processing (see Microbiological Evaluation of Clean Rooms and Other Controlled Environments <1116>) — A mode of processing pharmaceutical and medical products that involves the separate sterilization of the product and of the package (containers–closures or packaging material for medical devices) and the transfer of the product into the container and its closure under at least ISO Class 5 (see Table 1) conditions.

Beyond-Use Date (BUD) (see General Notices and Requirements and Pharmaceutical Compounding — Non-sterile Preparations <795>) — For the purpose of this chapter, the date or time after which a CSP shall not be stored or transported. The date is determined from the date or time the preparation is compounded.

Biological Safety Cabinet (BSC or Hood) — A ventilated cabinet for CSPs, personnel, product, and environmental protection having an open front with inward airflow for personnel protection, downward high-efficiency particulate air (HEPA) filtered laminar airflow for product protection, and HEPA filtered exhausted air for environmental protection. The BSC/Hood is considered to be a primary engineering control.

Buffer Area (or Buffer Zone/Area) — An area where the primary engineering control (PEC) is physically located. Activities that occur in this area include the preparation and staging of components and supplies used when compounding CSPs. (See also “Clean Room”)

Clean Room (see Microbiological Evaluation of Clean Rooms and Other Controlled Environments <1116> and also the definition of Buffer Area [or Buffer Zone/Area]) — A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. Microorganisms in the environment are monitored so that a microbial level for air, surface, and personnel gear are not exceeded for a specified cleanliness class. (See also “Buffer Zone”)

Compounding Aseptic Containment Isolator (CACI) — A compounding aseptic containment isolator (CACI) designed to provide worker protection from exposure to undesirable levels of airborne drug particulates throughout the compounding and material transfer processes and to provide an aseptic environment for compounding sterile preparations. Air exchange with the surrounding environment should not occur unless the air is first passed through a microbial retentive filter (99.97% HEPA minimum) system capable of containing airborne concentrations of the physical size and state of the drug being compounded.

Where volatile hazardous drugs are prepared, the exhaust air from the isolator should be appropriately removed by properly designed building ventilation. The interior of the CACI will always be under a negative pressure environment. The CACI is a primary engineering control.

Compounding Aseptic Isolator (CAI) — A form of isolator specifically designed for compounding pharmaceutical ingredients or preparations. It is designed to maintain an aseptic compounding environment within the isolator throughout the compounding and material transfer processes.

Air exchange into the isolator from the surrounding environment should not occur unless the air has first passed through a microbially retentive filter (99.97% HEPA minimum). The interior of the CAI will always be under a positive pressure environment. The CACI is a primary engineering control.

Critical Site — A location that includes any component or fluid pathway surfaces (e.g., vial septa, injection ports, beakers) or openings (e.g., opened ampuls, needle hubs) exposed and at risk of direct contact with air (e.g., ambient room or HEPA filtered), moisture (e.g., oral and mucosal secretions), or touch contamination. The risk of microbial particulate contamination of the critical site increases with the size of the openings and exposure time.

Direct Compounding Area (DCA) — A critical area within the ISO Class 5 (see Table 1) primary engineering control (PEC) where critical sites are exposed to unidirectional HEPA-filtered air, also known as first air.

Disinfectant — An agent that frees from infection, usually a chemical agent but sometimes a physical one (i.e., UVGI), and that destroys disease-causing pathogens or other harmful microorganisms but may not kill bacterial and fungal spores. It refers to substances applied to inanimate objects.

First Air — The air exiting a HEPA filter in a unidirectional air stream that is essentially particle free.

Inches Water Column (“ W. C.) — The differential pressure (dP or ΔP) reporting value from one area to another. The values may be expressed as either a positive or negative differential pressure.

Labeling [see General Notices and Requirements and 21 USC 321 (k) and (m)] — A term that designates all labels and other written, printed, or graphic matter on an immediate container of an article or preparation, or on, or in, any package or wrapper in which it is enclosed, except any outer shipping container. The term “label” designates that part of the labeling on the immediate container.

Laminar Air Flow Workstation (LAFW) — A form of isolator specifically designed for compounding pharmaceutical ingredients or preparations. It is designed to maintain an aseptic compounding environment within the isolator throughout the compounding and material transfer processes utilizing HEPA filtered horizontal and possibly vertical laminar airflow. The LAFW is considered to be a primary engineering control.

Media-Fill Test (see Microbiological Evaluation of Clean Rooms and Other Controlled Environments <1116>) — A test used to qualify aseptic technique of compounding personnel or processes and to ensure that the processes used are able to produce sterile product without microbial contamination.

During this test, a microbiological growth medium such as Soybean–Casein Digest Medium is substituted for the actual drug product to simulate admixture compounding. The issues to consider in the development of a media-fill test are media-fill procedures, media selection, fill volume, incubation, time and temperature, inspection of filled units, documentation, interpretation of results, and possible corrective actions required.

Multiple-Dose Container (see General Notices and Requirements and Containers for Injections under Injections <1>) — A multiple-unit container for articles or preparations intended for parenteral administration only and usually containing antimicrobial preservatives. The beyond-use date (BUD) for an opened or entered (e.g., needle-punctured) multiple-dose container with antimicrobial preservatives is 28 days (see Antimicrobial Effectiveness Testing <51>), unless otherwise specified by the manufacturer.

Negative Pressure Room — A room that is at a lower pressure than the adjacent space or spaces (considered to be an area(s) that is neutral in pressure) and, therefore, the net flow of air is into the room.

Air Offset — The difference between the volume of air mechanically supplied to a room/area versus the volume of air exhausted from a room/area. When the supply air is higher than the exhaust, the room/area will have a positive pressure environment. When the supply air is lower than the exhaust, the room/area will have a negative pressure environment. The higher the offset, the more pressure, either positive or negative in the room/area.

Pass-throughs – Pass-throughs are usually installed to pass drugs and CSP equipment from one area to the other without opening a door thereby allowing the exchange of air from the Anteroom/area to a Buffer Zone or from an area outside the Anteroom/area into that area. The pass-through should have a mechanism so that only one door of the pass-through can be opened at any given time. If the pass-through does not have this type mechanism, it should be retrofitted with same. The pass-through can be any type, such as: CSP element transfer box, refrigerator, drug storage, etc.

Pharmacy Bulk Package (see Containers for Injections under Injections <1>) — A container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes. The closure shall be penetrated only one time after constitution with a suitable sterile transfer device or dispensing set, which allows measured dispensing of the contents. The pharmacy bulk package is to be used only in a suitable work area such as a laminar flow hood (or an equivalent clean air compounding area).

Where a container is offered as a pharmacy bulk package, the label shall (a) state prominently “Pharmacy Bulk Package — Not for Direct Infusion,” (b) contain or refer to information on proper techniques to help ensure safe use of the product, and (c) bear a statement limiting the time frame in which the container may be used once it has been entered, provided it is held under the labeled storage conditions.

Primary Engineering Control (PEC) — A device or room that provides an ISO Class 5 (see Table 1) environment for the exposure of critical sites when compounding CSPs. Such devices include, but may not be limited to, laminar airflow workbenches (LAFWs), biological safety cabinets (BSCs), compounding aseptic isolators (CAIs), and compounding aseptic containment isolators (CACIs).

Preparation — A preparation, or a CSP, that is a sterile drug or nutrient compounded in a licensed pharmacy or other healthcare-related facility pursuant to the order of a licensed prescriber. The article may or may not contain sterile products.

Product — A commercially manufactured sterile drug or nutrient that has been evaluated for safety and efficacy by the FDA. Products are accompanied by full prescribing information, which is commonly known as the FDA approved manufacturer’s labeling or product package insert.

Positive Pressure Room — A room that is at a higher pressure than the adjacent space or spaces (considered to be an area(s) that is neutral pressure) and, therefore, the airflow is out of the room

Single-Dose Container (see General Notices and Requirements and Containers for Injections under Injections <1>) — A single-dose container is a single-unit container for articles (see General Notices and Requirements) or preparations intended for parenteral administration only. It is intended for a single use. A single-dose container is labeled as such. Examples of single-dose containers include prefilled syringes, cartridges, fusion-sealed containers, and closure-sealed containers when so labeled.

Segregated Compounding Area — A designated space, either a demarcated area or room, that is restricted to preparing low-risk level CSPs with 12 hour or less BUD. Such area shall contain a device that provides unidirectional airflow of ISO Class 5 (see Table 1) air quality for preparation of CSPs and shall be void of activities and materials that are extraneous to sterile compounding.

Sterilizing Grade Membranes — Membranes that are documented to retain 100% of a culture of 10 microorganisms of a strain of Brevundimonas (Pseudomonas) diminuta per square centimeter of membrane surface under a pressure of not less than 30 psi (2.0 bar). Such filter membranes are nominally at 0.22-µm or 0.2-µm porosity, depending on the manufacturer’s practice.

Sterilization by Filtration — Passage of a fluid or solution through a sterilizing grade membrane to produce a sterile effluent.

Terminal Sterilization — The application of a lethal process (e.g., steam under pressure or autoclaving) to sealed containers for the purpose of achieving a predetermined sterility assurance level of usually less than 10⁻⁶, or a probability of less than one in one million of a non-sterile unit

Unidirectional Flow — An airflow moving in a single direction in a robust and uniform manner and at sufficient speed to reproducibility sweep particles away from the critical processing or testing area.

As stated above, some of the requirements listed here are not necessarily of an engineering nature. We have included these to ensure a more comprehensive presentation.

Description: The immediate-use provision is intended only for those situations where there is a need for emergency or immediate patient administration of a CSP. Such situations may include cardiopulmonary resuscitation, emergency room treatment, preparation of diagnostic agents, or critical therapy where the preparation of the CSP under conditions described for Low-Risk Level CSPs subjects the patient to additional risk due to delays in therapy. Immediate-use CSPs are not intended for storage for anticipated needs or batch compounding. Preparations that are medium-risk level and high-risk level CSPs shall not be prepared as immediate-use CSPs.

Immediate-use CSPs are exempt from the requirements described for Low-Risk Level CSPs only when all of the following criteria are met:

1 The compounding process involves simple transfer of not more than three commercially manufactured packages of sterile nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers’ original containers and not more than two entries into any one container or package (e.g., bag, vial) of sterile infusion solution or administration container/device. For example, anti-neoplastics shall not be prepared as immediate-use CSPs because they are hazardous drugs.

2 Unless required for the preparation, the compounding procedure is a continuous process not to exceed 1 hour.

3 During preparation, aseptic technique is followed and, if not immediately administered, the finished CSP is under continuous supervision to minimize the potential for contact with non-sterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other CSPs, and direct contact of outside surfaces.

4 Administration begins not later than 1 hour following the start of the preparation of the CSP.

5 Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the CSP shall bear a label listing patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared the CSP, and the exact 1-hour BUD and time. If administration has not begun within 1 hour following the start of preparing the CSP, the CSP shall be promptly, properly, and safely discarded.

MAS Comments: These may not be compounded in an ISO 5 environment so extra caution is required to ensure the immediate use CSP does not come into contact with other contaminated items or surfaces. A segregated, non-traffic, area is desired for this type CSP.

Description: Hazardous drugs shall be stored separately from other inventory in a manner to prevent contamination and personnel exposure. Many hazardous drugs have sufficient vapor pressures that allow volatilization at room temperature; thus storage is preferably within a containment area such as a negative pressure room or cabinet. The storage area should have sufficient general exhaust ventilation, at least 12 air changes per hour (ACPH)⁴ to dilute and remove any airborne contaminants.

The negative pressure Buffer Zone/Area is sufficient, and may be utilized, for storing these drugs.

MAS Comments: This is an exception to the standard that requires all flat surfaces (including storage racks and/or cabinets) to be removed from a Buffer Zone/Area.

Description: All Primary Engineering Controls (LAFW, BSC, CAI and CACI) shall be placed in an ISO 7 Buffer Zone/Area for all risk level CSP. Only authorized personnel shall have access to this area when CSP operations are taking place.

Exceptions: When closed-system vial-transfer devices (CSTDs) (i.e., vial-transfer systems that allow no venting or exposure of hazardous substance to the environment) are used, they shall be used within the ISO Class 5 (see Table 1) environment of a BSC or CACI. In facilities that prepare a low volume of hazardous drugs, the use of two tiers of containment (e.g., CSTD within a BSC or CACI that is located in a non-negative pressure room) is acceptable. (This includes locating the CACI in the positive pressure Buffer Area/Area/Zone). Also:

CACIs shall be placed in an ISO Class 7 (see Table 1) buffer area unless they meet all of the following conditions:

Ø The isolator shall provide isolation from the room and maintain ISO Class 5 (see Table 1) during dynamic operating conditions, including transferring ingredients, components, and devices into and out of the isolator and during preparation of CSPs.

Ø Particle counts sampled approximately 6 to 12 inches upstream of the critical exposure site shall maintain ISO Class 5 (see Table 1) levels during compounding operations.

Ø Not more than 3520 particles (0.5 µm and larger) per m³ or 100 particles (0.5 µm and larger) per ft³shall be counted during material transfer, with the particle counter probe located as near to the transfer door as possible without obstructing the transfer.

Ø It is incumbent on the compounding personnel to obtain documentation from the manufacturer that the CACI will meet this standard when located in environments where the background particle counts exceed ISO Class 8 for 0.5-µm and larger particles.

MAS Comments: MAS has always advocated placing ALL Primary Engineering Control(s) in an ISO 7 Buffer Zone/Area. We also advocate having the entire CSP Areas enclosed with hard walls except where only low volumes of low and medium risk CSP are performed

Description: The ISO 7 Buffer Zone/Area shall be segregated from any surrounding unclassified areas and be accessed through an Anteroom/Area. When the Buffer Zone/Area is enclosed by walls it shall maintain a positive pressure of +0.02” - +0.05“ W. C. and have a minimum of 30 ACPH. Keep in mind this area is virtually identical to the physical design of a standard surgical suite (operating room).

The size of the room should be sufficient to allow space for the workstations, carts with CSP elements that are wheeled into the room and enough workspace for the pharmacist, pharmacy technician or other personnel to work comfortably. The Buffer Zone/area must be segregated from the Anteroom by a hard wall when high daily volumes of low and/or medium risk CSP are performed.

If a low average daily volume of low and/or medium risk CSP are performed then the Buffer Zone/Area can be segregated from an Ante-area by a demarcation line or soft barrier (i.e., plastic strips). The air movement must be from the Buffer Zone/Area to the Ante-Anteroom/Area. The velocity of the air movement must be a minimum of 40 feet per minute (FPM – this can be measured by a thermal or mechanical anemometer). Utilizing a soft barrier in this type of CSP area enables the measurement of the air velocity more accurate.

The minimum 30 ACH shall be delivered either by the Secondary Engineering Control device(s) (usually ceiling mounted laminar airflow units) or a combination of the Primary and Secondary Engineering Controls to achieve the 30 ACH. The air being provided and exchanged via the Primary and Secondary Engineering Controls shall be through a HEPA (High Efficiency Particulate Air) filter with a minimum starting efficiency of 99.97% at 0.3 microns whose efficiency shall be confirmed on a yearly basis.

The exhaust from this Buffer Zone shall be near the floor (under a door or a low HVAC return if possible) of the ISO 7. Exhausting air via ceiling return should be a second option and may, physically, be the only option available during a renovation.

MAS Comments: The current design of the positive pressure ISO 7 Buffer Zone/Area should be to provide a target of +0.03” W. C. (in an enclosed Buffer Zone/Area with +0.01 in the Anteroom giving the required minimum of 0.02” W. C. difference required by the standard) and 35 ACPH in that Buffer Zone/Area. The 35 ACPH, instead of the required 30 ACPH minimum, is preferable to account for filter loading that will occur over time.

Utilizing the primary engineering control’s HEPA filters to achieve the minimum 30 ACPH is not in keeping with traditional clean room design. The 30 ACPH should have the volume of air equal to the volume of a room/area mechanically supplied to or exhausted from that room/area. We expect this to be rectified sometime in the future. Other design elements are:

Excess capacity to achieve 40-60 ACPH should be designed into the secondary engineering controls when possible. The LAFW, BSC, CAI and/or CACI shall have more than sufficient supply of ultra-clean air to pass through the HEPA filters in these units. It should be noted that the pressure in the Buffer Zone/Area must always be significantly higher than the Anteroom/Area when there is a hard wall segregating these two areas. The difference, as stated above, is 0.02” W. C.

In enclosed ISO 7 Buffer Zone/Areas, the differential pressure (dP or ∆P) should be continuously monitored via a pressure sensing device. Keep in mind that the differential pressure in the ISO 7 room should be compared to a non-pressurized adjacent area such as the common pharmacy area or a hallway and not the Anteroom/Area. The same applies to monitoring the differential pressure of the Anteroom/Area.

Airflow dynamics (air mixing and air movement) is an integral part of the design of any pressurized room needing an ultra-clean air environment. The design must consider where doors, pass-throughs, other PEC and any other physical barriers that may be present. The primary concern is to evaluate what the airflow patterns will be after the installation of the Secondary Engineering Controls and the design should take into account that the LAFW, BSC, CAI and/or CACI is protected from any source of contamination.

The installation of return air grilles near the floor is usually a difficult procedure due to the construction and thickness of an existing wall and may be prohibitively costly. In some cases it may be unavoidable to have return air exiting the room via a ceiling or upper wall return as long as its placement does not allow for the possible contamination of the ISO 5 units. In many cases the excess air will exit the room under the entrance door to the ISO 7 Buffer Zone/Area into the Anteroom/Area.

The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets in the Buffer Zone/area shall be smooth, impervious, free from cracks and crevices, and non-shedding, thereby promoting cleanability and minimizing spaces in which microorganisms and other contaminants may accumulate.

The surfaces shall be resistant to damage by disinfectant agents. Junctures of ceilings to walls shall be coved or caulked to avoid cracks and crevices where dirt can accumulate. If ceilings consist of inlaid panels, the panels shall be coated or impregnated with a polymer or covering to render them impervious and hydrophobic, and they shall be caulked or gasketed around each perimeter to seal them to the support frame.

Walls may be constructed of flexible material (e.g., heavy gauge polymer), panels locked together and sealed, or of epoxy-coated (or other impervious coating) gypsum board.

Preferably, floors are overlaid with wide sheet vinyl flooring with heat-welded seams and coving to the sidewall are preferred.

Dust-collecting overhangs, such as ceiling utility pipes, and ledges, such as windowsills, should be avoided. The exterior lens surface of ceiling lighting fixtures should be smooth, mounted flush, and sealed. Any other penetrations through the ceiling or walls shall be sealed.

The Buffer Zone/area shall not contain sources of water (sinks) or floor drains.

Work surfaces shall be constructed of smooth, impervious materials, such as stainless steel or molded plastic, so that they are easily cleaned and disinfected.

Carts should be of stainless steel wire, nonporous plastic, or sheet metal construction with good quality, cleanable casters to promote mobility. Storage shelving, counters, and cabinets shall be smooth, impervious, free from cracks and crevices, non-shedding, cleanable, and disinfectable; their number, design, and manner of installation shall promote effective cleaning and disinfection.

Description: The ISO 7 Buffer Zone/Area that is used for High Risk CSP (Hazardous Drugs – i. e., Chemo) shall be segregated from the Anteroom/Area by a wall and shall be accessed from the Anteroom/Area. The Buffer Zone/Area, enclosed by wall(s), shall maintain a minimum negative pressure of -0.01” W. C. minimum and have a minimum of 12 ACPH. Keep in mind this area is virtually identical to the physical design of a standard Airborne Infectious Isolation (AII) room.

The minimum 12 ACH shall be delivered either by the Secondary Engineering Control device (usually ceiling mounted laminar airflow units) or a combination of the Primary and Secondary Engineering Controls to achieve the minimum 12 ACPH.

The air being provided and exchanged via the Primary and Secondary Engineering Controls shall be through a HEPA (High Efficiency Particulate Air) filter with a minimum starting efficiency of 99.97% at 0.3 microns whose efficiency shall be confirmed on a yearly basis.

The exhaust creating negative pressure from these rooms is usually provided by a Hood/BSC. 100% of the exhaust from the Hood/BSC should be vented to the outside via dedicated ducting. A “booster fan” where the air exits the building may be required to exhaust a sufficient volume of air to attain the desired negative pressure in the area. In a Buffer Zone/Area where there is a CAI or CACI mechanical air moving devices may be required to achieve the desired negative pressure.

Exceptions: In facilities that prepare a low average daily volume of hazardous drugs, the use of two tiers of containment (e.g., CSTD within a BSC, CAI or CACI that is located in a non-negative pressure room) is acceptable. It is strongly recommended locating a BSC, CAI or CACI in the positive pressure Buffer Area/Zone.

MAS Comments: To adhere to “cleanroom” design criteria, we design the negative pressure ISO 7 Buffer Zone/Area to provide a minimum of -0.02” W. C. and 35 ACH instead of 12 ACPH in that Buffer Zone/Area.

Utilizing the primary engineering controls HEPA filters to achieve to minimum 30 ACPH is not in keeping with traditional clean room design. The 30 ACPH should have the volume of air equal to the volume of a room/area mechanically supplied to or exhausted from that room/area. We expect this to be rectified sometime at a later date. Other design elements are

Description: An enclosed Anteroom/Area is defined as a positive pressure area with an ISO Class 8 or better environment maintaining a nominal +0.01” W. C. differential pressure. All positive pressure Buffer Zone/Areas shall have and Ante-area or Anteroom that is segregated from the areas adjacent.

A negative pressure Buffer Zone/Area for High Risk CSP must have an Anteroom. If the negative pressure Buffer Zone has a common Anteroom with a positive pressure Buffer Zone/Area, then the minimum ISO requirement for the Anteroom is ISO 7.

The positive pressure in an enclosed Anteroom/Area plus Buffer Zone (with no intervening wall) shall be continuously monitored in relation to the area outside the room.

The size of the room should be sufficient to allow space for the storage of CSP elements for a set duration of time. This will be dependent upon available space and the desires of the pharmacy management and staff. It must be of sufficient size to allow for a hand washing and gowning station.

An Ante-area that is not enclosed may have a demarcation line between it and the Buffer Zone but the entire area must be segregated from the adjacent outside areas with a hard wall. The Anteroom/Area may be physically separated from the adjacent areas around it with only a demarcation line to segregate it from any surrounding areas when only a low daily average volume of low and medium risk CSP are performed.

The demarcation line of an Ante-Area from a Buffer Zone/Area or an area surrounding the Anteroom/Area itself may be as simple as a line painted on the floor or may be a barrier of plastic strips or another type of soft non-porous barrier.

MAS Comments: Placing the entire CSP unenclosed area (Buffer Zone/Area and Anteroom/Area) in any location will usually require some type of barrier to segregate the Buffer Zone/Area on at least three sides. It is recommended that, for a low volume of Low and Medium Risk CSP, this is acceptable and we always recommend that a barrier of plastic strips be used to separate the Anteroom/Area from the Buffer Zone/Area. It is usually a good engineering practice to separate the Anteroom/Area from the adjacent outside areas with this type barrier. Other design elements are:

1. General – The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets in the buffer area shall be smooth, impervious, free from cracks and crevices, and non-shedding, thereby promoting cleanability and minimizing spaces in which microorganisms and other contaminants may accumulate. The surfaces shall be resistant to damage by disinfectant or sterilizing agents. Buffer Zones should have as few flat surface areas inside the room as possible.

2. Pressure Monitoring – A pressure gauge or velocity meter shall be installed to monitor the pressure differential or volume airflow between the Buffer Zone and the Anteroom/Area and between the Anteroom/Area and the general environment outside the compounding area. All compounding rooms (Buffer Zone/Areas) must use a common neutral pressure area and not use the Anteroom as a reference. It should have both visual and audible alarming capability. The results shall be reviewed and documented on a log at least every work shift (minimum frequency shall be at least daily) or by a continuous recording device. The pressure between the ISO Class 7 (see Table 1) and the general pharmacy area shall not be less than 5 Pa (0.02 inch water column).

3. Ceilings – Junctures of ceilings to walls shall be coved or caulked to avoid cracks and crevices where dirt can accumulate. If ceilings consist of inlaid panels, the panels shall be impregnated with a polymer to render them impervious and hydrophobic, and they shall be gasketed or caulked around each perimeter to seal them to the support frame.

All lights, fire sprinklers, smoke/flame sensors, temperature and humidity sensors and any security equipment must be sealed so that air cannot pass between the pressurized area and the plenum above the ceiling.

4. Walls – Walls may be constructed of flexible material (e.g., heavy gauge polymer), panels locked together and sealed, or of epoxy-coated gypsum board. Preferably, floors are overlaid with wide sheet vinyl flooring with heat-welded seams and coving to the sidewall. Dust-collecting overhangs, such as ceiling utility pipes, and ledges, such as windowsills, should be avoided. The exterior lens surface of ceiling lighting fixtures should be smooth, mounted flush, and sealed.

5. Anteroom/area Door – The primary entrance door leading into the Anteroom/area must be sealed on the top and sides with either make-up air moving under the door. If there are multiple doors leading into the Anteroom/area then all doors, other than the primary door, should be sealed on the top, sides and bottom. All doors must have an automatic door closer that will close the door securely from a full open position in five (5) seconds or less.

6. Buffer Zone Doors – The primary entrance door leading into a Buffer Zone must be sealed on the top and sides with either make-up or excess air moving into or out of the room under the door. Except in rare instances, there should be a primary entrance/exit door. All other doors should be sealed on the top, sides and bottom. The door should be “hands free” to open and must have an automatic door closer that will close the door securely from a full open position in five (5) seconds or less. A standard knob or handle for exiting the Buffer Zone is acceptable

7. Floors – Preferably, floors are overlaid with wide sheet vinyl flooring with heat-welded seams and coving to the sidewall. The top of the coving should be sealed with a 100% silicone sealant. If flat vinyl flooring is laid down, then the flooring must be sealed at the wall. Any baseboard, if installed, must be sealed on the top and bottom.

8. Wall and Ceiling Penetrations – All penetrations through the ceiling or walls shall be sealed. This can be accomplished with gaskets or 100% silicone rubber sealant.

9. Pass-throughs – Pass-throughs are usually installed to pass drugs and CSP equipment from one area to the other without opening a door thereby allowing the exchange of air from the Anteroom/area to a Buffer Zone or from an area outside the Anteroom/area into that area. The pass-through should have a mechanism so that only one door of the pass-through can be opened at any given time.

10. Sinks/Drains/Work Surfaces in the Buffer Zone/Area – The Buffer Zone/Area shall not contain sources of water (sinks) or floor drains. Work surfaces shall be constructed of smooth, impervious materials, such as stainless steel or molded plastic, so that they are easily cleaned and disinfected.

11. Sinks and Gowning Area in the Anteroom/Area – The hand washing and gowning station for pharmacy personnel must be in the Anteroom/Area. The sink must be a “hands free” type.

12. Carts – Carts should be of stainless steel wire, nonporous plastic, or stainless steel sheet metal construction with good quality, cleanable casters to promote mobility.

13. Anteroom/Area Storage – Storage shelving, counters, and cabinets shall be smooth, impervious, free from cracks and crevices, non-shedding, cleanable, and disinfectable; their number, design, and manner of installation shall promote effective cleaning and disinfection.

14. Engineering Control Performance Verification – PECs (LAFWs, BSCs, CAIs, and CACIs) and secondary engineering controls (buffer and ante-areas) are essential components of the overall contamination control strategy for aseptic compounding. As such, it is imperative that they perform as designed and that the resulting levels of contamination be within acceptable limits. Certification procedures such as those outlined in ‘Certification Guide for Sterile Compounding Facilities’ (CAG-003-2006) shall be performed by a qualified individual no less than every 6 months and whenever the device or room is relocated or altered or major service to the facility is performed

15. Total Particle Count Analysis – Certification that each ISO classified area, for example, ISO Class 5, 7, and 8 (see Table 1), is within established guidelines shall be performed no less than every six (6) months for low and medium risk areas (ISO 7) and no less than one (1) month for high risk areas (ISO 7) or whenever the LAFW, BSC, CAI, or CACI is relocated or the physical structure of the buffer area or ante-area has been altered. Testing shall be performed by qualified operators using current, state-of-the-art electronic equipment calibrated yearly to NIST traceable standards with results of the following:

Ø ISO Class 5: not more than 3520 particles of 0.5 µm and larger size per cubic meter (100 particles of 0.5 µm and larger size per cubic foot) of air for any LAFW, BSC, CAI, and CACI;

Ø ISO Class 7: not more than 352,000 particles of 0.5 µm size and larger per cubic meter (10,000 particles of 0.5 µm and larger size per cubic foot) of air for any buffer zone;

Ø ISO Class 8: not more than 3,520,000 particles of 0.5 µm size and larger per cubic meter (100,000 particles of 0.5 µm and larger size per cubic foot) of air for any Anteroom/area.

16. Sampling Plan – An appropriate environmental sampling plan shall be developed for airborne viable particles based on a risk assessment of compounding activities performed. Selected sampling sites shall include locations within each ISO Class 5 (see Table 1) environment and in the ISO Class 7 and 8 (see Table 1) areas and in the segregated compounding areas at greatest risk of contamination (e.g., work areas near the ISO Class 5 [see Table 1] environment, counters near doors, pass-through boxes). Refer to Microbiological Evaluation of Clean Rooms and Other Controlled Environments <1116> and the CDC’s ‘Guidelines for Environmental Infection Control in Healthcare Facilities, 2003’ for more information on sampling methodology.

17. Air Sampling Devices – The sampling for pathogen testing must be performed no less than every 6 months for low and medium risk areas (ISO 7) and no less than one month for high risk areas (ISO 8) preferably with an active air sampling device. There are a number of manufacturers of electronic active air sampling equipment. It is important that personnel refer to the manufacturer’s recommended procedures when using the equipment to perform volumetric air sampling procedures. A sufficient volume of air (400 to 1000 liters) shall be tested at each location in the room being tested in order to maximize sensitivity. The volumetric air sampling devices need to be serviced and calibrated to NIST traceable standards as recommended by the manufacturer. This is preferable to static agar plates placed in the CSP Area.

18. Cleaning Schedule – Cleaning and disinfecting surfaces in the LAFWs, BSCs, CAIs, and CACIs are the most critical practices before the preparation of CSPs. Consequently, such surfaces shall be cleaned and disinfected frequently, including at the beginning of each work shift, before each batch preparation is started, every 30 minutes during continuous compounding periods of individual CSPs, when there are spills, and when surface contamination is known or suspected from procedural breaches.

Work surfaces in the ISO Class 7 (see Table 1) buffer areas and ISO Class 8 (see Table 1) ante-areas as well as segregated compounding areas shall be cleaned and disinfected at least daily, and dust and debris shall be removed when necessary from storage sites for compounding ingredients and supplies using a method that does not degrade the ISO Class 7 or 8 (see Table 1) air quality (see Disinfectants and Antiseptics <1072>).

Site	Minimum Frequency
ISO Class 5 (see Table 1) Primary Engineering Control (e.g., LAFW, BSC, CAI, CACI)	At the beginning of each shift, before each batch, not longer than 30 minutes following the previous surface disinfection when ongoing compounding activities are occurring, after spills, and when surface contamination is known or suspected
Counters and easily cleanable work surfaces	Daily
Floors	Daily
Walls	Monthly
Ceilings	Monthly
Storage shelving	Monthly

MAS Comments: As stated above, some of the revisions and changes listed here are not necessarily possible in all pharmacies. Space limitations and the physical layout or geometry of the area where the CSP operations are performed may not always lend itself to a “perfectly designed” CSP area. For the most part, as long as the intent to comply as much as is possible with USP <797> is attempted and that the actual air environment of the area where the CSP is taking place is within acceptable parameters, this may be adequate. The State Board of Pharmacy may have published requirements that will assist in your design decisions.

It should be noted that having the Primary and Secondary Engineering Controls are not a substitute for proper procedures and protocols for the personnel performing the CSP. The importance of having proper personal protective equipment (PEC - correct gloves, gowns, head coverings, shoe covering, etc.) and abiding by the Standard Operating Procedures (SOP) are paramount. Most all contamination other than cross-contamination of drugs will usually come from the humans performing the CSP operation. As an example, humans without protective garments generate the following:

· The act of sitting down or standing up generates about 2,500,000 particles/ft³.

5) Positive pressure Buffer Zone/Area should be significantly higher in pressure than the Anteroom/Area by +0.02 “ W. C. or greater

1) +0.01” W. C. (Maintaining a minimum pressure difference between the Anteroom/Area and a Buffer Zone at ±0.02: W. C.)

2) The room should be an ISO 8 environment with only an I. V. compounding room or ISO 7 with both a positive I. V. compounding a negative compounding Buffer Zones

Laminar Air Flow Workstations (LAFW), Biological Safety Cabinets (BSC) and Compounding Aseptic Isolator (CAI and CACI)

1) Should be placed in their respective Buffer Zone/Area. If they are countertop units, they need to be placed on a plain stainless steel table (no drawers or storage under the table).

2) Primary Engineering Controls will utilize air from the Buffer Zone/Area for the horizontal and/or vertical laminar flow air stream.

3) Negative pressure barrier isolators for high risk CSP may import air from the Buffer Zone/Area but this air cannot be recirculated back into the room, it must be vented to the outside through dedicated ducting.

4) Negative pressure barrier isolators for high risk CSP must have a dedicated exhaust to the outside.

1) Must be provided through a minimum 99.97% HEPA filter with the filter at the entry point of the room where possible

3) In virtually all cases the air should be provided by a fan-driven unit. Most facility HVAC systems do not have the capacity to provide the volume of air needed through a HEPA filter for ACH and to maintain a constant air delivery

1) Air from a positive pressure room should be vented from the room via exhaust grilles that are located near the floor whenever possible. In some cases this may not be practical and the exhaust will be in other areas of the room.

2) In positive pressure rooms, air may be vented under the door into the Anteroom/Area.

3) Air from a negative pressure room or a negative pressure barrier isolator where high risk CSP is being performed must be vented to the outside (usually via the hood/BSC).

1) Exhaust air should be vented from the room via exhaust grilles that are located near the floor whenever possible. In some cases this may not be practical and the exhaust will be in the area directly outside of the room.

1) Should not be stored in the Buffer Zone/Area if at all possible as many flat surfaces as possible should be removed from the room. The exception is the storing of High Risk compounding drugs in the negative pressure Buffer Zone.

2) With the High Risk exception above, all supplies should be stored in the Anteroom/Area or Anteroom/Area. All prep for drugs and personnel should be accomplished in this room.

3) An Anteroom/Area (separated by a curtain or demarcation line) is only acceptable if there is a low volume of low and medium risk CSP performed on an average day.

1) All furniture and equipment not essential to the CSP operation should not be in the Buffer Zone/Area. It should be removed to outside the area.

2) If there are horizontal flat surfaces that cannot be removed from the area then a procedure should be in place to clean these flat surfaces with biocidal type cleaning agent before each working day to prevent contamination of CSP elements.

3) All surfaces should be able to withstand cleaning with biocidal type cleaning agents. It is advisable that the compounding personnel do the actual cleaning of the CSP area to ensure sterile conditions.

1) Should be a “clean room” type ceiling that is non-porous and gasketed with either “hold down” clips or other retaining devices for the ceiling tiles. In some instances a sealed drywall ceiling can be used provided there are access hatches installed in the ceiling to access overhead laminar flow equipment. Care should be taken to not have a ceiling in place that, under positive pressure, would lift ceiling tiles and allow contaminated air into the CSP area via the Venturi effect.

2) A ceiling specifically designed for positive pressure room applications is recommended for this type room. Simply using glue as a sealant in a standard drop ceiling is not sufficient.

3) All ceiling equipment and fixtures (lighting, sprinkler heads, etc.) should be flush with the ceiling itself and withstand cleaning with a biocidal type cleaning agent.

4) The ceiling, if installed as part of a renovation, must be sealed so that no air movement can occur between the working area and the interstice space above the room.

2) Walls that have to be created with wallboard (drywall) or prefabricated walls that can be erected in situ must also meet this requirement.

1) Floors should be one contiguous covering with no cracks, crevices or seams where pathogen growth could occur including baseboards. Preferably, floors are overlaid with wide sheet vinyl flooring with heat-welded seams and coving to the sidewall are preferred.

2) If a tiled floor is existing then it should be removed and a contiguous floor installed or a heat sealed polymeric covering be installed over top of the existing tiled floor.

3) All floor surfaces or coatings must be able to withstand cleaning with biocidal type cleaning agents.

4) All baseboards should be sealed and must be able to withstand cleaning with biocidal type cleaning agents.

1) Doors must have an automatic door closer that will close the door from a full open position in less than five (5) seconds. All primary doors must have a minimum ½” gap on the bottom of the door with the top and sides being gasketed. All non-primary doors must be sealed on all four (4) sides.

1) Any pass-through should have a mechanism so that only one door of the pass-through can be opened at any given time so that no exchange of air can occur between two (2) areas during operation of the pass-through. The pass-through can be any type, such as: CSP element transfer box, refrigerator, drug storage, etc.

1) The placement of the air purification systems (APS) is critical in ensuring that the air that the LAFW’s and/or barrier isolators intake is pure, uncontaminated air, which, after passing through the workstation’s filter(s), makes it ultra-pure. Ideally, the ultra-pure air should be delivered a fan/filter unit. Rarely can the house HVAC system deliver the volume of air needed in a consistent volume to maintain air changes and room pressure.

2) Perfect air mixing is only possible when there are no mobile elements in a room (room at rest). A room designed for perfect air mixing will only be so until a person enters the room and disrupts the airflow pattern. The addition upper room ultraviolet germicidal irradiation (UVGI) devices to ensure that the least risk of pathogen contamination can occur during the compounding operation. This is not covered in USP <797>, but, it is added protection against pathogen contamination.