Designing An Environmental Monitoring Program For Non-Sterile Manufacturing: A Risk-Based Approach

Microbial control for non-sterile manufacturing helps to ensure the safety and efficacy of pharmaceuticals. Products that are compromised with excessive amounts of microorganisms, specified microorganisms, or objectionable microorganisms may not be effective or could be dangerous to consumers. Unfortunately, the regulations governing non-sterile manufacturing are not as clear or as abundant as those for sterile manufacturing. This leads many manufacturers to utilize risk assessment analysis tools to adapt portions of sterile manufacturing guidelines when developing environmental monitoring programs for non-sterile environments.

According to 21 CFR 211.113(a): “Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.”¹ To control and prevent objectionable microorganism contamination, many concepts applied to sterile manufacturing can be useful sources for non-sterile manufacturing. As some microbial isolate are expected to be present in non-sterile manufacturing, gaining an overall understanding of the product and the manufacturing process is important in protecting the consumer. A portion of this knowledge lies within a well-established environmental monitoring (EM) program.

This article describes one acceptable method of establishing an environmental monitoring program for non-sterile manufacturing.

Establishing Where To Sample

Environmental monitoring is an important instrument to gain an understanding of microbial contamination sources. Monitoring trends in the environment assist in ensuring that procedures for preventing contamination are effective and that the facility is in a state of control. In an EM program, the air is sampled for viable and nonviable particulates. In addition, surfaces are sampled for microbial contamination. If microorganisms are recovered, their identification can be used to help identify potential sources of the contamination and any corrective and preventive actions that may be required.

USP <1116> states that “it is not possible to recommend microbial control levels for each type of manufacturing environment.” Risk analysis should be used and should include a rationale for the sampling locations, the frequencies for each monitored environment, and alert and action levels of the data.² Developing a fit-for-purpose EM program for non-sterile manufacturing facilities can be established utilizing risk assessment tools (e.g., failure mode effects analysis [FMEA], hazard analysis critical control points [HACCP], or Ishikawa [aka fishbone analysis] in a tabular style).

I recommend using a phased approach in conjunction with established guidelines and risk assessment analysis when qualifying an area for environmental monitoring. The environmental monitoring performance qualification (EMPQ) phased approach can consist of up to five phases that can be adjusted as needed. This approach can be used for new or renovated facilities, as well as sterile or non-sterile environments.

When selecting the sites to be sampled, it is recommended to utilize established guidelines. For example, ISO 14464-1:2015 contains a table used to establish the number of nonviable (total) particulate samples required based on the size of the room to be monitored.

A common approach in determining where to monitor includes obtaining a map of the room, gridding the room into equal sections, and using the risk assessment results — close to critical process, high traffic area, difficult-to-clean areas, proximity to utilities or drains, personnel flow, material flow, storage areas, potable water usage, air flow patterns, spatial coverage, construction materials, etc. The obtained information is then used to plot out where in the grid the sample(s) should be taken. Samples should be collected at the sites identified to contain the highest risk of contamination. Surface and active viable samples are typically taken at these locations, and as part of the EMPQ. Note that all risk assessment decisions should be documented.

A Phased Approach To Environmental Monitoring Performance Qualification (EMPQ)

Once the sample sites have been established, the phased approach can begin. Phases 3 through 5 (defined below) can all occur on the same day, but they must occur during three separate manufacturing (or filling) events. The study duration will be dependent upon the manufacturing operations timelines. The Guidance for Industry “Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice” published in 2004 by the Food and Drug Administration is a good resource that briefly describes initial cleanroom qualifications.

Phase 1: Baseline Monitoring — Baseline monitoring should occur once, after the initial construction cleaning and prior to the sanitization of the facility. Representative microorganisms can be identified to help catalog the resident microbial flora of the facility.

Phase 2: Static Monitoring — Static monitoring should occur after the facility sanitization, while no activities are occurring in the room. The monitoring should take place on three separate days.

Phase 3: Dynamic No-Manufacture Monitoring — This monitoring can occur with personnel working in the area, but product manufacturing should not be in progress. This monitoring should occur on three separate days, typically spread out over a few weeks, depending on the process.

Phase 4: Dynamic Manufacture Monitoring — This monitoring can occur during manufacturing operations and on the same days as the dynamic no-manufacture monitoring, if manufacturing has begun. However, it must occur after the dynamic no-manufacturing monitoring has been sampled.

Phase 5: At Rest/Recovery — This monitoring occurs approximately 15 to 20 minutes³ after the manufacturing operations have occurred and prior to cleaning operations. This data is used to measure how quickly the rooms can bounce back to an ‘at rest’/static state.

Action limits during the EMPQ may be implemented and modified (if needed) from the sterile regulatory guidelines (e.g., Annex 1, USP <1116>, ISO 14464-1, and the Parenteral Drug Association Technical Report 13 [PDATR 13]) or via risk assessment. Alert limits are typically established after some historical data has been generated and evaluated. The decision and rationale for interim limits should be documented.

How Often To Sample

Following the qualification activities, the data from the EMPQ should be evaluated to recommend an interim routine EM monitoring program. Depending on the data, sites may be added or removed to establish an interim EM program that is suitable for the intended purpose of the non-sterile manufacturing operation. Non-sterile manufacturing operations necessitate a different microbial control strategy than sterile manufacturing environments, and non-sterile environments can endure relatively infrequent environmental monitoring.³ I recommend a minimum routine monitoring frequency of at least monthly to gather relevant information regarding the environment. Monitoring at a more infrequent basis while establishing a robust fit-for-purpose program will limit the available data for scientific risk based decisions.

After the sample sites have been chosen, the limits have been established, and the monitoring frequencies have been determined, routine monitoring may begin using the interim EM program. 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.”³

I recommend that the interim EM program be monitored for a minimum of one year to collect baseline data and to evaluate seasonal fluctuations. Following the year of data collection, the environmental monitoring trend data may indicate a reduction in sample frequency or sampling locations can be adequately justified. Again from Annex 1: “On the basis of long-term observations, manufacturers may increase or decrease sampling at a given location or eliminate a sampling location altogether.”³

Establishing Alert Limits

EM action limits may be implemented and modified (if needed) from the sterile regulatory guidelines (e.g. Annex 1, USP <1116>, ISO 14464-1, and the Parenteral Drug Association Technical Report 13 [PDATR 13]). Alert limits should be based on historical data and should be used as an early warning system for processes that drift from their established state of control.⁴ Utilizing 50 percent of the action level without proper justification is not scientifically sound and may be frowned upon during regulatory audits. Statistical analysis can be performed on trend data to establish alert limits based on the process capabilities of the facility. It is common to establish alert limits using a 95 percent confidence interval, where 95 percent of the samples will pass the established alert limit.⁴ The decision and rationale for the established limits, sampling frequency, and sample sites should be documented.

Other Considerations

Other considerations in the EM program, including the EMPQ, are media selection, incubation schemes (e.g., single-temperature, dual-tier incubation, temperature ranges, incubation timeframes), recovery methods (e.g., contact plates, swabbing, equipment, sample volume), out-of-limit responses, and data trending. These considerations may appear to be somewhat standardized in the industry, but differences do exist. For example, some companies may only utilize tryptic soy agar with neutralizers for all EM samples in a two-tier transfer incubation scheme. Other companies may rationalize that Sabouraud dextrose agar should be used periodically for the recovery of yeast and molds in a single-tier incubation scheme. Both methods are acceptable, but the rationale and supporting data should be clearly documented with scientific rationale.

The considerations for sample sites, monitoring frequency, alert/action levels, media, incubation schemes, recovery methods, out-of-limit responses, and data trending should be clearly defined and included in the EMPQ, as well in the environmental monitoring procedures. The clearly detailed procedures will help ensure that the monitoring is performed consistently to gather scientific data that can be utilized to make informed decisions regarding the manufacturing environment.

Conclusion

Ensuring products are not contaminated with objectionable microorganisms is not only a regulatory requirement — it is essential in ensuring consumer safety. The first step in achieving this goal is understanding the overall manufacturing process and the associated contamination control processes. The risks, the manufacturing process, the product (e.g., the route of administration, the excipients, the intended consumer, the microbial load of all the excipients, the water activity of the product), the utilities, the product packaging, and the environmental control parameters are all important knowledge points required to control and prevent product contamination.

Developing an EMPQ for non-sterile manufacturing to monitor and control manufacturing environments is one component of ensuring safe products. Non-sterile manufacturing operations necessitate a different microbial control strategy than sterile manufacturing environments.³ Establishing the EMPQ and subsequent EM program for non-sterile manufacturing can be accomplished utilizing risk assessment tools and adapting portions of the regulations for sterile manufacturing guidelines, where appropriate, for the non-sterile manufacturing process.

References:

1. Code of Federal Regulations 21 CFR 211, Subpart F, Section 211.1113 - Control of Microbiological Contamination.
2. USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments
3. Annex 1 - European Commission EudraLex "The Rules Governing Medicinal Products in the European Union" Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 1 - Manufacture of Sterile Medicinal Products, 25Nov08.
4. Parenteral Drug Association Technical Report 13 [PDATR 13])- Fundamentals of an Environmental Monitoring Program, PDA 2014.

About the Author:

Crystal M. Booth is president of Azzur Labs, LLC. She has over 19 years of experience in pharmaceutical microbiology, working in quality assurance, CDMOs, R&D, and quality control laboratories, including startup companies. During her career, she has developed and validated methods for antibiotics, otic products, topical creams, topical ointments, oral solid dose products, oral liquid dose products, veterinary products, human parenterals, vaccines, biologics, aseptically filled products, and terminally sterilized products. Those methods include microbial limits testing, bacterial endotoxins testing, particulate testing, sterility testing, pharmaceutical water system validations, EM programs, surface recovery validations, disinfectant efficacy studies, minimum inhibitory concentration testing, antimicrobial effectiveness testing, hold time studies, and various equipment validations. Booth earned her bachelor’s degree in biology from Old Dominion University and her master’s in microbiology from North Carolina State University.