Significant pressure is being placed on hospital pharmacies to ensure compliant compounding operations in the face of increasing scrutiny from government regulators, state boards of pharmacy, and health care accrediting agencies. As these bodies are focusing on the gamut of pharmaceutical compounding, there is an expectation that pharmacies are operating at USP <797> standards, and in some cases, current Good Manufacturing Practices (cGMPs) as well. Integral to maintaining the standards set forth by both USP <797> and cGMPs is a comprehensive and robust environmental monitoring (EM) program.
Part 1 of this feature—Impact of USP <797> on Environmental Monitoring—delves into the structure and implementation of a proper program, as well as the regulatory divergence of USP <797> and cGMPs. Presented here, part 2 discusses the inevitable excursions that will take place within a sterile compounding environment and how best to manage them.
This article is the second part of a 2-part feature focusing on the impact of the expected USP <797> revisions on environmental monitoring, as well as the influence of cGMPs.
Part 1 of this feature—Impact of USP <797> on Environmental Monitoring—is available at: pppmag.com/article/1839
Differentiating Trends and Isolated Incidents
In several instances, the tenets of USP <797> and cGMPs related to EM are similar, and 503A hospital and compounding pharmacies may benefit from assimilating these tenets from both sets of documents. For example, USP <797> and cGMPs both establish non-viable and viable particle limits to control the environment in which CSPs are prepared (as well as acceptable differential pressures, detailed in Part 1 of this feature), as shown in TABLE 1. When an excursion occurs (ie, the colony forming unit [CFU] limits are exceeded), the pharmacy must determine why it occurred and if it unfavorably affected the CSPs that were prepared during the time of the excursion. More important, if any adverse trends appear, they must be aggressively addressed, as they are indicative of a system that is not properly controlled.
When an excursion is identified, it can be analyzed by reviewing the limits for a particular classified area, such as ISO 5. TABLE 1 shows that within an ISO 5 area, active air samples should consistently yield between zero and one CFU per cubic meter.
With this backdrop, let us consider a hypothetical example resulting from EM sampling within an individual ISO 5 biological safety cabinet (BSC). In this example, the active air samples were consistently within the expected range of 0 - 1 CFU/m3 for nine consecutive days; on the tenth day, 2 CFU were isolated, and the samples returned to less than 1 CFU per day for the next three days. In this case, the single excursion was not repeated, and therefore, it could be considered an isolated incident, not a trend.
To account for isolated excursions, pharmacies should have an investigation procedure that includes the following elements:
- A requirement that no additional excursions are found during the next three sampling periods
- A review of laboratory data to ensure the excursion was not lab related
- Reexamination of all operations associated with the preparation of the CSP (eg, pressure differential, the latest BSC certification, personnel monitoring, preparation of disinfection solutions, and cleaning)
- A review of other CSPs prepared during the same time period to ensure they pass sterility tests
- Identification of the microorganism (to the genus level at a minimum). If the organism is a pathogen or other objectionable microorganism, the pharmacy should conduct a risk analysis to determine whether the microorganism would adversely affect the integrity of the CSP, and whether it can be eliminated via current disinfection processes
If the investigation shows the excursion was an isolated incident that would not affect product quality or safety, no additional actions would be needed. However, if the hypothetical scenario above led to the discovery of 2 or more CFUs for 4 consecutive days, the pharmacy should conclude this is a trend and conduct an extended investigation that includes steps 1 through 5 above, and incorporates the following elements as well:
- A review of data from adjacent ISO areas, such as BSCs, PECs, or HVAC systems, and a review of HEPA filters for damage
- A review of all personnel involved in preparing CSPs during the testing period to determine whether staff has been involved in other incidents. This review should encompass any changes in personnel garbing or other work practices
- A historic review of personnel conducting the EM sampling
- A historic review of personnel training (including media fills)
- Termination of operations and comprehensive cleaning and sanitization of the area, followed by successful EM results for three consecutive days
- Revalidation of the area if EM trends continue
- Re-qualification of disinfection solutions to ensure effectiveness against American Type Culture Collection (ATCC) and in-house microorganisms
These measures are necessary to restore the area to a state that maintains an environment conducive to proper preparation of CSPs.
The primary purpose of USP <797> is to guide practitioners in properly maintaining the microbiological integrity of CSP preparation areas and the CSPs themselves. As detailed above, any CFU counts that exceed respective action levels should prompt a reevaluation of the adequacy of personnel work practices, cleaning procedures, and operational procedures, as well as air filtration efficiency within the aseptic compounding location and adjacent locations. An investigation into the source of the contamination must be conducted and the risk to the CSP determined. USP <797> and cGMPs agree on these points.
However, it is important to note there is a major difference between <797> and cGMPs regarding identification of EM microorganisms. The cGMP Aseptic Processing guidance requires routine identification of microorganisms to the species (or, where appropriate, genus) level… At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments [ISO 8] at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective)1.
Although USP <797> does not specifically dictate identification of microorganisms, it implies identifications should be conducted: Highly pathogenic microorganisms (eg, Gram-negative rods, coagulase positive staphylococcus, molds, and yeasts) can be potentially fatal to patients receiving CSPs and must be immediately remedied, regardless of CFU count, with the assistance of a competent microbiologist, infection control professional, or industrial hygienist3.
To address this difference, and more important, to maintain an environment that is conducive to the preparation of CSPs, a pharmacy should have a policy requiring that any microorganism isolated from an ISO 5 area is identified, and selected organisms isolated from ISO 7 and 8 areas will be identified on a monthly basis. This practice will provide information regarding the normal microbial flora that exist in the pharmacy, identify any changes to the flora, and indicate whether the cleaning and disinfecting solutions being used are efficacious in eradicating microorganisms that are isolated. In essence, this approach will facilitate process improvements (eg, modification of gowning and aseptic processes) resulting in the sustainable microbiological health of the pharmacy.
Additional USP <797> and cGMP Comparisons
Maintaining a clean environment is an essential step in producing CSPs that are free from extraneous microbiological and particulate contaminants. The key components to be monitored in a hospital pharmacy (as well as compounding pharmacies, outsourcing facilities, and manufacturing facilities) are personnel, air, and surfaces. Compounding personnel represent the greatest threat to the safety and efficacy of a CSP and must be fully trained to demonstrate aseptic skills, including passing practical and written evaluations (eg, gowning procedures, fingertip testing, air and surface monitoring), and participating in successful semiannual media fills. Likewise, clean surfaces are mandatory to minimize the potential of microbiological contamination; thus, hospital pharmacies must have a written cleaning and monitoring program to achieve clean and disinfected surfaces.
USP <797> and cGMPs agree that environmental monitoring begins with well-designed and constructed facilities. A well-regulated facility must have a robust EM program that includes viable, non-viable, and pressure differential monitoring. Non-viable monitoring is conducted with particle monitoring devices, to ensure the minimization of particulate contamination. Viable particle monitoring should be conducted with active air sampling devices, although settling plates are also acceptable.
Differential pressure monitoring ensures the unidirectional flow of air from high-risk areas (ISO 5) to lower-risk areas (ISO 7 and 8). Pressure gauges or velocity meters must be installed and the results must be reviewed and documented on a log after every work shift.
The frequency of HEPA filter leak testing is greater in cGMPs than in USP <797> and annual recertification should be adopted by pharmacy to prevent CSPs from being subjected to extraneous airborne contaminants. Overall, pressure differentials and smoke testing are very similar between the two documents.
Ultimately, an environmental sampling plan must be developed based on a risk assessment of compounding activities performed in specific pharmacies. In all cases, the data must be reviewed and microorganism trends investigated to prevent adverse changes within the environment.
USP <797>—a comprehensive chapter outlining the requirements for preparing CSPs—is similar to cGMPs in that it emphasizes procedures and practices that reduce microbiological, chemical, physical, and endotoxin contamination and variability. When inspecting manufacturing facilities, and more recently, compounding pharmacies, the FDA uses a six-system model that focuses on the Quality system as a whole, and the five systems that support Quality: Production, Facilities and Equipment, Laboratory Controls, Materials, and Packaging and Labeling.
Microbiological trending is a critical consideration for all compounding pharmacies and both USP <797> and cGMPs are essentially in agreement on this subject. While identification of microorganisms differs between the two documents, following cGMPs (ie, identification of all microorganisms found in ISO 5 areas) will facilitate process improvements (eg, modification of gowning and aseptic processes) resulting in the sustainable microbiological health of the pharmacy.
1. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice. US Department of Health and Human Services. Food and Drug Administration. September, 2004. www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf Accessed April 29, 2016.
2. The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S). www.picscheme.org Accessed April 29, 2016.
3. USP General Chapter <797> Pharmaceutical Compounding—Sterile Preparations.
Frank Settineri, BS, MS, has over 30 years’ experience working with a range of entities from compounding pharmacies to pharmaceutical companies, focusing on investigations, root cause analysis, microbiological data deviations, particulate matter mitigation, and cGMP compliance. He is particularly adept in writing responses to 483s and warning letters that result in both interim controls and sustained cGMP compliance. Frank is president and founder of Veracorp LLC, a consulting firm with a client base including compounding pharmacies, sterile facilities, API manufacturers, oral dosage manufacturers, and microbiology laboratories.
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