Facilities need to keep up with the changes in USP Chapters <795> Pharmaceutical Compounding – Nonsterile Preparations and <797> Pharmaceutical Compounding – Sterile Preparations. Both chapters have undergone significant updates, and to remain compliant, it is essential to understand the revised requirements. This webpage serves as an overview of the major changes related to facility design and construction requirements as compared to the previous chapter.
USP Chapter <795>
USP <795> Pharmaceutical Compounding – Nonsterile Preparations discusses the production of compounded nonsterile preparations. Part of the update to USP <795> is the section that handles the compounding of Hazardous Drugs into USP General Chapter <800>. This summary will focus only on the facilities involved in compounding nonsterile preparations that are not classified as Hazardous Drugs.
The previous version of USP <795> did not have many requirements for the compounding area. It simply stated that compounding must be performed in a “designated area” without any additional specifications. The updated <795> introduces more specific requirements for the compounding area. It specifically states that compounding must occur within an area that is used for compounding exclusively, and no other activity shall occur in this area. It states that the method of designation must be specified in your SOP. What this means is that you can separate out the compounding area by whatever means makes sense for your facility. This could mean that the area is physically separated by walls, or that the area is separated by something like a line of demarcation. The main purpose is to ensure that there is no contamination of the compounded drug by anything that should not be within the compounding area. The compounding area also now has some requirements for materials of construction that were not previously specified. The use of carpet as flooring within the compounding area is now explicitly prohibited.
Under the aforementioned version of USP <795>, there was no provision for any manipulations to be performed under any sort of containment. In the updated <795>, a “closed-system processing device” is now required while weighing, measuring, and/or otherwise manipulating components that could generate airborne particles. This means that if powder is being manipulated in any way, it should be performed under a powder containment hood.
The prior version of <795> stated that water shall be available for hand washing and equipment washing. It required the use of a minimum standard of water that meets the EPA’s Drinking Water Regulations. It also stated that purified water should be used for final rinsing of equipment and utensils. The requirements in the revised <795> are mostly unchanged. The standard of water being EPA Drinking Water was removed. It also expanded on the use of Purified Water by including distilled water and reverse osmosis water (which are just two different methods of purifying water). The primary difference is the inclusion of the requirement for the sink to be clean and emptied of all non-compounding equipment prior to washing compounding equipment. This is primarily a way of stating that washing should be done in a dedicated area and not co-mingled with items unrelated to compounding (e.g., dishes used in the consumption of food and drink).
The biggest change in facility requirements in the updated <795> is related to the conditions in which compounded drugs are stored and compounded. In the previous version of <795>, it only stated that “appropriate” temperature and humidity monitoring should be maintained “as required.” In the updated <795>, temperature and humidity monitoring requirements are explained in much greater detail. It states that the temperature in the storage area must be monitored. This can be accomplished manually using a log, in which the temperature is written down at least once daily that the facility is open. This can also be accomplished by the use of a continuous monitoring system that records and stores data in a log that can be retrieved on demand. The devices that are used for monitoring temperature must be calibrated at least once every 12 months.
The facility must also have a method of detecting and reducing the risk of temperature excursions. When a temperature excursion occurs, an investigation into the impact on the product or materials must occur, and the product must be discarded if quality has been compromised. A continuous monitoring system will have the ability to do this automatically by inputting high and low limits into the system – this system should be described in an SOP. If the temperature is recorded manually, the SOP will have to describe in full how temperature excursions are detected and the investigation process when it occurs.
USP Chapter <797>
USP <797> Pharmaceutical Compounding – Sterile Preparations discusses the production of compounded sterile preparations. A recent USP <797> update is the removal of the section that handles the compounding of Hazardous Drugs into USP General Chapter <800>. This summary will focus only on the facilities involved in compounding sterile preparations that are not classified as Hazardous Drugs.
Facility Design and Environmental Controls
The updated <797> provides a lot more detail into the materials of construction and fit and finish of facilities that engage in sterile compounding than the previous version. The previous version mostly described the concept of separation provided by a cleanroom but did not provide a lot of specific design criteria for the construction of these cleanrooms. In addition to facility design details on construction materials, it also describes some operational issues that should be considered when operating in these rooms.
The previous version of <797> recommended having HEPA filtered air introduced at the ceiling with returns mounted low on the wall. In the updated <797>, it is required for the HEPA filters to be installed into the ceiling and be at the terminal location (i.e., at the very end) of the ductwork. The returns are required to be low mounted on the wall unless a visual smoke study demonstrates an absence of stagnant airflow where particulate can accumulate. It is highly recommended that the air returns are mounted low on the wall to avoid performing a smoke study on the entire room, making it difficult to prove that air is not stagnant anywhere. The use of seals and sweeps at doors between the buffer rooms and anteroom is also not recommended. When considering the use of seals and sweeps at doors in a cleanroom setting, Eagle recommends not using them anywhere. Tacky mats are now also prohibited from being used within ISO classified areas.
The previous <797> only had provisions for the number of air changes per hour (ACPH) in ISO 7 classified rooms. The updated <797> also specifies the number of air changes per hour within an ISO 8 classified space, with the minimum being 20 ACPH; 15 of which must come from the HVAC system.
All pre-sterilization activities, such as weighing and mixing, must now be performed in a minimum of an ISO 8 classified room, and this activity must occur under containment (e.g., CVEs, BSCs, CACIs, or single-use glove bags). When performing both non-sterile compounding and sterile compounding, the respective containment hoods should be placed within separate rooms. Both can be compounded within the same room only when the containment hoods are placed 1 meter apart, neither are performed simultaneously, and the room must maintain ISO 7 standards during all operations, as demonstrated through certification.
All requirements for materials for construction of the cleanroom still apply, with one requirement slightly changed. In the previous <797>, the use of sheet vinyl flooring with heat-welded seams was recommended. In the updated <797>, no specific material is recommended, but rather the floor has to be non-shedding, non-porous, non-absorptive, and crack and crevice-free. While sheet vinyl certainly meets all these criteria, other options fit these requirements, such as a poured epoxy floor.
The previous version of <797> had a recommendation only for temperature within the cleanroom. The updated <797> provides a recommendation for maintaining temperature under 20˚C as well as maintaining relative humidity at 60% or lower. The temperature and humidity of the cleanroom must be monitored. This can be accomplished manually using a log, in which the temperature and humidity are written down at least once daily that the facility is open. This can also be accomplished using a continuous monitoring system that records and stores data in a log that can be retrieved on demand. The devices that are used for monitoring temperature and humidity must be calibrated at least once every 12 months. To maintain these temperature and humidity requirements, it is typical to employ the use of air conditioning equipment and potentially humidifiers or dehumidifiers. These pieces of equipment must not be free-standing within the cleanroom environment.
The previous version of <797> did not have any criteria listed for water sources. In the updated <797> there are requirements and recommendations for the systems within the cleanrooms that use water, which are in addition to those laid out within the updated <795>. It is now recommended that hands-free operation of sinks is utilized. These could be operated via a foot pedal, automatic sensors, etc. The anteroom is now prohibited from having floor drains. This does not include drains that are in the bottom of sinks but is limited to open drains that are on the floor. There is now a provision for sprinkler systems to be recessed into the ceiling and covered with a smooth, cleanable cover. These sprinkler covers will not be sealed to the ceiling; most have either a magnetic base or fit snugly into the hole of the ceiling tile.
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