ISO requirements for Compounding Sterile Pharmacies (CSP’s)
Expectations of USP <797>
USP <797> F identifies that compounding personnel represent the greatest threat to the safety and efficacy of a CSP, and as such, these personnel must be fully trained prior to preparing any type of CSP. Training should include live/electronic instructional sources (where possible), professional and up-to-date publications in aseptic principles, and demonstration of aseptic skills. Personnel must pass practical and written evaluations (eg, gowning procedures, fingertip testing, air and surface monitoring) and participate in successful semiannual media fills.
Individuals who do not achieve these criteria must be immediately re-instructed and re-evaluated by expert compounding personnel to ensure all deficiencies are corrected. Media fill challenge testing, in which sterile fluid bacterial culture media is transferred via a sterile syringe and needle into a sterile container, is the most practical way to evaluate an individual’s skills in aseptic preparation. F
USP <797> states that procedural guidance and practice begins with well-designed and well-constructed facilities, wherein the preparation area (usually ISO 5) F is surrounded by areas of lower classifications, in this case ISO 7, 8, thereby creating a unidirectional airflow from the ISO 5 area (positive pressure) through the ISO 7 area (lower positive pressure area) to the ISO 8 (still lower positive pressure) area to an unclassified area (zero positive pressure, e.g. corridor). A robust sterile operations program must include non-viable, viable, and pressure differential monitoring F. Non-viable monitoring is conducted with particle monitoring devices (a non-continuous monitoring device) and ensures the minimization of particulate contamination. These devices are also referred to as “particle counters.”
Viable particle monitoring should be conducted with active air sampling devices (continuous monitoring device). An environmental sampling planF must be based on a risk assessment of the compounding activities performed. Selected sampling sites must include locations within each ISO Class 5, 7, and 8 area, and the plan should detail the sample locations, methods of collection, sampling frequencies, volume of air sampled, and time of day related to activity in the compounding area. The data must be reviewed and any upward trends investigated to ensure there are no adverse changes within the environment. Additionally, isolation of pathogenic or objectionable microorganisms must be investigated.
(Pic of typical cleanroom layout)
Differential pressure monitoring ensures the unidirectional flow of air from high pressure (ISO 5) to lower pressure (ISO 7 and 8) areas. Pressure gauges or velocity meters must be installed and the data reviewed and documented in a log every work shift (or at a minimum, daily). Alternatively, a continuous recording device (i.e. digital data logger and chart recorder – TV2 Cleanroom Monitor) can be used). The pressure difference between the ISO Class 7 and the general pharmacy area must be at least 5 Pascals (Pa) (0.02 inch water column). In facilities where low– and medium-risk level CSPs are prepared, the differential airflow must be maintained at a minimum velocity of 0.2 meters per second (40 feet per minute) between the buffer and ante areas.
Taking into consideration human error and standard risk calculations F, the best solution is using automated chart recorders, and data loggers, to ensure USP requirements for monitoring differential air pressure.
Expectations of USP <797>vs cGMPs
To minimize the potential of microbiological contamination, clean, disinfected surfaces are mandatory and a written cleaning and monitoring programF is required. The current industry standard practice is to use three disinfectants:
- Sterile isopropyl alcohol for disinfection of surfaces, instruments, and gloves
- A quaternary ammonium or phenolic product for daily and weekly disinfection
- A sporicidal agent (eg, accelerated hydrogen peroxide) for monthly disinfection or when microbiological spores are isolated
Surface monitoring will verify the surfaces are within established microbiological limits. A major difference between USP <797> and Current Good Manufacturing Practice regulations enforced by the FDA (cGMPs)F is that the latter requires disinfection qualification studies to demonstrate that disinfectants are efficacious against standard American Type Tissue Collection (ATTC) microorganisms and in-house isolates. Although these studies are expensive, time consuming, laborious, and not required by <797>, FDA may ultimately require they be conducted by a hospital pharmacy.
Both USP <797> and cGMPs require that surface sampling be performed in all ISO classified areas on a periodic basis using contact plates or swabs; <797> requires it be done at the conclusion of compounding. Sample locations must be defined in the EM planF or on a form and should include surface wipe sampling of the working areas in biological safety cabinets (BSCs); compounding aseptic containment isolators (CACIs); counter tops where finished preparations are placed; areas adjacent to BSCs and CACIs, including the floor directly under the work area; and patient administration areas. An investigation must be conducted when trends or pathogens/objectionable microorganisms are found.
Regulatory Divergence Between USP <797> and cGMPsF: The requirements of cGMPs are general and provide an overview of what is necessary for manufacturing facilities to produce safe and efficacious products. Interestingly, <797> sometimes provides more details than cGMPs.
HEPA Filter Leak Test
HEPA filtration, for example, is not mentioned in cGMPs and the only reference to air filtration is in it’s section § 211.46 Ventilation, air filtration, air heating and cooling: (c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas. If air is recirculated to production areas measures shall be taken to control recirculation of dust from production. In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants. In contrast, <797> states: All HEPA filters shall be efficiency tested using the most penetrating particle size and shall be leak tested at the factory and then leak tested again in situ after installation.
However, FDA fills this and other cGMP voids by publishing Industry Guidance reportsF. For example, the Aseptic Processing guidance includes a section on HEPA filtration that recommends performing leak testing for each HEPA filter twice a year; USP <797> does not provide a definitive frequency for conducting leak testing. In this instance, FDA may expect a hospital pharmacy to follow cGMPs (the Aseptic Processing guidance) and conduct leak testing twice a year. Considering that HEPA filters produce unidirectional air that contacts surfaces and components used to prepare CSPs, this expectation is not unrealistic and should be adopted by pharmacy to ensure CSPs are not subject to extraneous airborne contaminants.
A similar situation exists with differential pressures. USP <797> includes a section entitled, Pressure Differential Monitoring F that states, A pressure gauge or velocity meter shall be installed to monitor the pressure differential or airflow between the buffer area and the ante-area and between the ante-area and the general environment outside the compounding area. The results must be reviewed and documented on a log at least every work shift (minimum frequency, at least daily) or by a continuous recording device like the TV2 by Two Dimensional Instruments, LLC. The pressure differential between the ISO Class 7 and the general pharmacy area shall not be less than 5 Pa (0.02 inch water column). In facilities where low- and medium-risk level CSPs are prepared, differential airflow shall maintain a minimum velocity of 0.2 meters per second (40 feet per minute) between buffer area and ante-area.
The cGMP Aseptic Processing guidance also includes a section on pressure differentials and mentions the term numerous times. For example, it states that an essential part of contamination prevention is the adequate separation of areas of operation. To maintain air quality, it is important to achieve a proper airflow from areas of higher cleanliness to adjacent, less clean areas. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. For example, a positive pressure differential of at least 10-15 Pascals (Pa) should be maintained between adjacent rooms of differing classification (with doors closed). When doors are open, outward airflow should be sufficient to minimize ingress of air, and it is critical that the time a door can remain ajar be strictly controlled.
Given that cGMP expectations for pressure differentials are more stringent than <797>, it may appear that following cGMPs imposes an unnecessary burden. However, most BSCs and LAFWs are designed to achieve differential pressure and air flows that adhere to cGMP requirements, and a pharmacy simply needs to have these measurements certified twice a year to demonstrate they are compliant with both <797> and cGMPs.
USP <797> and cGMPs differ on smoke studies, but the differences are minor. For example, <797> states, In situ air pattern analysis via smoke studies shall be conducted at the critical area to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Whereas, the Aseptic Processing guidance states, Smoke studies and multi-location particle data can provide valuable information when performing qualification studies to assess whether proper particle control dynamics have been achieved throughout the critical area. As neither document provides details related to frequency, compliance to both documents can be achieved by conducting smoke studies during initial installation and after any biannual leak test that does not meet the recertification requirements.
The pressure on hospital pharmacies to ensure compounding operations are compliant is only increasing as regulators, from state boards of pharmacy to accrediting agencies, are inspecting compounding practices and expecting compliance to USP <797> and, in some cases, cGMPs. Even hospital pharmacies that operate as 503A facilities should be cognizant of cGMP requirements. In fact, the close similarities between <797> and cGMPs related to environmental monitoring provide a strong argument for hospital pharmacists to not only educate themselves on both regulations, but also to consider implementing EM practices that achieve the aims set forth in both documents.