Tamika Cathey Independent Consultant EAS Consulting Group
Contamination can cost you. Recalls and fines for problematic products can result in hundreds of millions in costs. The US FDA requires contamination prevention—not just in the food industry—but in cosmetics, dietary supplements, biologics, medical devices and pharmaceuticals as well. These requirements are established to ensure product safety and reduce the likelihood of adverse events 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 helps evaluate a cleaning program’s effectiveness in preventing contamination.
Employ a systematic scientific approach to establish an effective EMP, considering the risk of contamination within the manufacturing process. If implemented appropriately, an EMP acts as an early warning sign to prevent contaminated products. Consider a few basic concepts when establishing an EMP:
1. EM team—Gather 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.
2. 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. FDA guidance documents like “Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice” are useful tools 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. 3. Contaminants—Predict the 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.
3. Route of Entry—Identify possible routes of entry. 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. Continuous routine monitoring can help determine additional routes of entry once the EMP is established.
4. Risk Assessment—Perform a risk analysis to determine all areas of possible contamination. Areas close to critical processes, 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. This assessment should be a part of your original EM setup and performed as additional data trends are identified on a yearly basis.
5. Sampling Plan and Mapping—Select sampling sites by utilizing 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.” 7. Limits—Set EMP action limits based on 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).
Once the EMP has been completed, practical implementation of routine EM monitoring can be easily established and justified because it is based upon risk and empirical data sources. For example, surfaces and personnel can be monitored after critical operations (e.g. daily etc.) and weekly air sampling (static and dynamic) can be ex 0ecuted. Yearly evaluation of EM data should be performed to identify action level trends, introduction of new microorganisms into a facility, new routes of entry or sources of contamination that could impact the quality of your finished products. Overall, it is critical to establish an appropriate Environmental Monitoring Program because it is the foundation of routine monitoring practices, identification of sources of contamination, and developing effective Corrective Action and Preventive Action (CAPAs) to address any problems that are discovered by your organization.
About the Author
Tamika Cathey consults with an international client base on regulations pertaining to safety and quality of pharmaceuticals and dietary supplements. She evaluates client compliance readiness by conducting audits, risk assessments and mock FDA/GMP investigations and works to design improvement programs based on findings.
Tamika has a B.S. in Biology from Greensboro College in North Carolina. Prior to consulting she held positions such as Associate Director, Regulatory Affairs for Charles River Laboratories, and Consumer Safety Officer at FDA’s Atlanta District.