By Crystal M. Booth, PSC Biotech
Trending environmental monitoring (EM) data is a regulatory requirement. However, it is useful in obtaining significant information about the facility. Trends can help determine if a facility is in a state of microbial control and relay the environmental monitoring data to facility management in a meaningful format. In this two-part article exploring environmental monitoring trending, I look first at the regulations and guidelines around EM. In part two, I will discuss tools and best practices for using the trends to ensure that an efficient environmental monitoring program is established.
EM is a required, essential component of current good manufacturing practices (cGMP). It is used to measure and monitor the microbial bioburden levels in a facility and to determine if the facility is in a state of microbial control. EM consists of many different data points that culminate in a single program. Some of the data points in EM include:
- Non-viable particulates
- Active viable air samples
- Passive viable air samples (also known as settle plates or fall-out plates)
- Surface samples (e.g., contact plates and/or swabs)
- Personnel monitoring
- Microorganism identifications
- Some companies include water system monitoring and/or compressed gas system monitoring in their EM trending program as well.
Analyzing the data generated from EM one data point at a time can be difficult to decipher and the overall health of the facility environment may be misinterpreted. EM trending helps to overcome this difficulty. EM trends examine data over time to look for changes or movements in a general direction. The Parenteral Drug Association Technical Report 13 (PDA TR13) describes trend analysis as “a review performed in response to an alert or action condition. This review provides an analysis of specific environmental monitoring data to identify adverse trends.”1
EM trending can be performed for many reasons, including:
- Regulatory compliance
- Ensuring a state of control of the facility
- The ability to be proactive before a problem gets out of hand
- To provide a graphical representation of the data
- To determine any problem areas in the facility
- To determine if the cleaning and disinfection program is working as expected
- Monitoring the microbial flora of the facility and seasonal trends
- Providing a simpler means of communication of the EM data to management
- Identifying sources of microbial contamination.
- Establishing alert and action levels
There are a multitude of acceptable configurations in which the data can be presented in EM trend reports due to the various components of the EM program. The importance of performing EM trending has been demonstrated repeatedly and this importance has not been lost on regulators. The Pharmaceutical Microbiology Manual published for the FDA states that each laboratory is required to monitor and trend data to ensure compliance and detect any abnormalities.2
Regulations And Guidance Documents
Regarding regulations and guidelines, there are many sources that mention the need for EM and trending. The following excerpts from various sources is not intended to be an all-inclusive list.
- 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.”3
- 21 CFR 211.113(b): “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.”3
- FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice (2004).4
- “The quality control unit should provide routine oversight of near-term (e.g., daily, weekly, monthly, quarterly) and long-term trends in environmental and personnel monitoring data. Trend reports should include data generated by location, shift, room, operator, or other parameters. The quality control unit should be responsible for producing specialized data reports (e.g., a search on a particular isolate over a year period) with the goal of investigating results beyond established levels and identifying any appropriate follow-up actions. Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data.” 4
- “In aseptic processing, one of the most important laboratory controls is the environmental monitoring program. This program provides meaningful information on the quality of the aseptic processing environment (e.g., when a given batch is being manufactured) as well as environmental trends of ancillary clean areas. Environmental monitoring should promptly identify potential routes of contamination, allowing for implementation of corrections before product contamination occurs (21 CFR 211.42 and 21 CFR 211.113).” 4
- European Commission EudraLex (2014), The Rules Governing Medicinal Products in the European Unition, Volume 4 “EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use,” Part 1, Chapter 6: Quality Control, 6.9 “Some kinds of data (e.g., tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any out of trend or out of specification data should be addressed and subject to investigation.”5
- PIC/S (2007) Document PI 012-3, “Recommendation on Sterility Testing.” 10.6 “Records should be maintained of the numbers and type of organisms isolated and results presented in a format that facilitates early detection of trends. Routine identification of environmental microorganisms to at least the genus level should assist in detecting trends. Sensitive techniques such as molecular typing techniques will be required for identification of microorganisms if equivalence of identity of environmental and test isolates is the sole rationale used to invalidate the original sterility test (refer to clause 13.1).”6
- United States Pharmacopeia (USP) <1116> Microbiological Control and Monitoring of Aseptic Processing Environments.7
- “The analysis of contamination trends in an aseptic environment has long been a component of the environmental control program.”7
- “Data from a routine microbial environmental monitoring program that can be related to time, shift, facility, etc. This information is periodically evaluated to establish the status or pattern of that program to ascertain whether it is under adequate control. A trend analysis is used to facilitate decision-making for requalification of a controlled environment or for maintenance and sanitization schedules.”7
- FDA (2020) Pharmaceutical Microbiology Manual (PMM), Document Number ORA.007, Revision 02. “Each laboratory is required to monitor and trend data to ensure compliance and detect any abnormalities.”2
- Parenteral Drug Association Technical Report 13 (PDA TR13) Fundamentals of an Environmental Monitoring Plan (2014). “To effectively execute microbiological, surveillance support systems, a documented system should be in place for identifying excursions and adverse trends; in addition, a feedback mechanism should be implemented for verification of effectiveness of any action taken in response to data. All data should be documented and trended.”1
A multitude of warning letters and regulatory observations regarding trending have been written. An FDA 483 observation dated May 2, 2014 stated that “[REDACTED] Water trending records are not always accurate or supported by raw data. Specifically, the [REDACTED] Water System Microbial Analysis Results tables for the [REDACTED] of [REDACTED] included test results for Total Combined Mold & Yeast counts, and Total Coliform Count. None of the [REDACTED] water samples submitted for microbiological analysis during this time were analyzed for these two specific tests. The [REDACTED] Water System Microbial Analysis Results tables were approved by Quality Assurance. Note: Total Combined Mold & Yeast counts, and Total Coliform count are not required tests for [REDACTED] Water.”8
This observation demonstrates that regulators will ask to review environmental monitoring trending reports and raw data. Be prepared and ensure that trending reports are accurate, properly reviewed, and performed in a timely manner.
Another FDA 483 observation dated Oct. 2, 2014 stated “observation #s IA, 9 and 10 cited during the previous inspection of 2012 on inadequate Quality Unit Oversight since 2007 to identify adverse trend of molds, investigate adverse trends, and implement corrective actions to
prevent reoccurrence of molds in the manufacturing environment were again noted during this inspection in the firm's [REDACTED] vaccines manufacturing buildings' Grades [REDACTED] environmental classified areas. The firm currently has implementation corrective actions completion date of Q4 2017 for the adverse molds contamination in [REDACTED] of the manufacturing buildings.”8
This observation demonstrates that regulators will follow up on past inspection action items as well as ask to review environmental monitoring trending reports and raw data. Be sure to have any past commitment items from previous inspections properly closed out and documented.
An FDA warning letter dated May 13, 2020 discusses environmental monitoring and trending by stating “your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)) …In response to this letter, provide a comprehensive, independent and retrospective review of personnel and environmental monitoring data since 2018. This review should include your assessment and corrective action and preventive action (CAPA) for your environmental monitoring program (including personnel monitoring) to ensure the CAPA supports robust environmental control of your aseptic processing facility. The assessment and CAPA, including any recommendations from the independent review, should include justification of sampling locations, frequency of sampling, alert and action limits, adequacy of sampling techniques, and the trending program. See FDA’s guidance document, Sterile Drug Products Produces by Aseptic Processing – current Good Manufacturing Practice, to help you meet the cGMP requirements when manufacturing sterile drugs using aseptic processing, at https://www.fda.gov/media/71026/download.”8
The second part of this series will look at tools and best practices for using EM trends to ensure that an efficient and successful environmental monitoring program is established.
I would like to thank my PSC Biotech colleagues AyCee Carter and J Alexander Thompson for their review of this article.
- Parenteral Drug Association Technical Report 13 (2014) Fundamentals of an Environmental Monitoring Plan.
- Food and Drug Administration (2020) Pharmaceutical Microbiology Manual, Document Number ORA.007, Revision 02. Accessed on 24Mar2021 at https://www.fda.gov/media/88801/download
- Code of Federal Regulations (CFR) Title 21: Food and Drugs. Accessed on 24Mar2021 at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm
- Food and Drug Administration (FDA) Guidance for Industry (2004). Sterile Drug Products Produced by Aseptic Processing- Current Good Manufacturing Practice. Accessed on 24Mar2021 at https://www.fda.gov/media/71026/download
- European Commission EudraLex (2014), The Rules Governing Medicinal Products in the European Unition, Volume 4 “EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use”, Part 1, Chapter 6. Accessed on 23Mar2021 at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2014-11_vol4_chapter_6.pdf
- PIC/S (2007) Document PI 012-3 “Recommendation on Sterility Testing.” Accessed on 23Mar2021 at https://www.gmp-compliance.org/files/guidemgr/PI%20012-3%20Recommendation%20on%20Sterility%20Testing.pdf
- United States Pharmacopeia (USP) <1116> Microbiological Control and Monitoring of Aseptic Process Environments. USP 43-NF38.
- FDA Warning Letters Database. Accessed on 24Mar2021 at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters
About the Author
Crystal M. Booth, M.M., is a regional manager at PSC Biotech and has over 20 years of experience in pharmaceutical microbiology, environmental monitoring, and quality assurance.She obtained her master’s degree in microbiology from North Carolina State University.Crystal is a seasoned award-winning technical writer and author of Method Development and Validation for the Pharmaceutical Microbiologist.During her career, Crystal has worked in microbiology, consulting, quality assurance, CDMOs, R&D, and quality control laboratories.Crystal has developed and validated numerous microbial methods and has worked with many different product types.