By Tamika Cathey
Contamination prevention is a requirement across many regulated industries such as foods, cosmetics, dietary supplements, biologics, medical devices and pharmaceuticals. These requirements are established to ensure product safety and reduce the likelihood of an adverse event(s) for the consumer. Regulated industries can meet specified requirements by setting and maintaining environmental controls as part of their Good Manufacturing Practice (GMP) quality system to prevent product contamination.
An Environmental Monitoring Program (EMP) is a critical tool to understanding the types of contamination sources and levels of microbiological activity within a GMP facility. Monitoring trends within the environment using an EMP can assist in the evaluation of the effectiveness of cleaning programs, personnel practices, and production operations to limit or prevent contamination.
A systematic scientific approach is needed in order to establish an effective EMP considering the risk of contamination within the manufacturing process. If implemented appropriately, it acts as an early warning sign for the prevention of contamination in product. A few basic concepts should be considered when establishing an effective EMP:
- Gather an EM team– This should be a committee with subject matter experts experienced in performing risk assessments. The team should include, at a minimum, representatives from Quality, Microbiology, Facilities and Production.
- Regulations and Guidance– Identify all applicable statutes, compendia, regulatory, and/or guidelines based upon product classification, route of administration, and the types of GMP activities performed. Guidance documents like “FDA Guidance for Industry “Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice” can be a useful tool clarifying existing rules and outlining regulatory expectations. Risk assessment analysis tools can be used to adapt portions of the sterile guidelines where regulations for non-sterile manufacturing are not as clear.
- Identify Contaminants- Identify common types of contaminants that can be introduced to the GMP facility and/or product. Microorganisms such as bacteria, yeasts, and molds, and coliforms as well as pathogens like E. Coli, Salmonella, Listeria, and S. Aureus are potential microbiological contaminants; chemical contaminants may include a variety of entities including heavy metals, pesticides, and residual solvents but allergens are certainly a high priority; and physical contaminants such as metal can all be identified from both incoming raw materials and the production process. Compendia sources such as the United States Pharmacopeia (USP), Chapter <2023>, Microbiological Attributes of Nonsterile Nutritional and Dietary Supplements, can provide a framework for microbial attributes for non-sterile nutritional and dietary supplements.
- Route of Entry– Routes of entry should also be identified; personnel, equipment, utilities (HVAC systems, for example) and production processes are a few common sources for contamination. A firm’s supply chain can also introduce material and component contamination due to poor GMP practices. Knowing these common sources is the first step in developing a strategy on what to sample for and where to sample throughout a facility.
- Risk Assessment– A risk analysis is performed to determine all areas of possible contamination. Areas close to critical process, high traffic areas, difficult-to-clean facility locations and equipment, personnel and material flow, and storage areas are all places that can easily be identified by utilizing risk assessment tools like failure mode effects analysis [FMEA], hazard analysis critical control points [HACCP], or Ishikawa [aka fishbone analysis] tables. A documented thorough risk assessment will include cross-contamination concerns, a rationale for sampling locations, frequencies for each monitored environment, and alert and action levels for each type of potential contaminant.
- Sampling Plan and Mapping– When selecting sites to be sampled, it is recommended to utilize established guidelines. For example, ISO 14464-1:2015 contains tables to establish the number of nonviable particulate samples based on the size of the room. A common approach in determining where to monitor includes obtaining a map of the area and using the risk assessment results to plot out where the sample(s) should be taken. According to EU GMP Annex 1, “Environmental monitoring sampling plans should be flexible with respect to the monitoring frequencies, and sample plan locations should be adjusted based on the observed rate of contamination and ongoing risk analysis.”
- Setting Limits- EMP action limits may be implemented and modified from the sterile regulatory guidelines provided in ISO 14464-1, Annex 1, and others such as USP <1116>. Alert limits should be based on historical data and should be used as an alert tool for processes that drift from their state of control. Statistical analysis can be performed on trend data to establish these alert limits as they pertain to the process capabilities of the facility. The decision and rationale for the established limits, sampling frequency, and sample sites should then be documented with instructions in a written procedure or standard operating procedure (SOP).