In pharmaceutical companies, we frequently use the thought process that says we have an environmental monitoring program, which was validated and now it is good forever. We do not routinely go back and reassess the program to ensure that it meets current regulatory expectations and requirements. We also tend to think that because we are only making non-sterile products, there is not as much need for a comprehensive program as if you were manufacturing sterile products. Unfortunately, both of these propositions are incorrect.
Increasingly the regulators are imposing the same expectations for an environmental monitoring program on non-sterile manufacturers as they are for sterile manufacturers. Additionally, the expectations of the entire program has expanded in recent years. (Anonymous, 2017)
This article describes the current expectations for an environmental monitoring program.
Since the early 1990’s there has been an increased emphasis on the need for environmental monitoring by many different regulatory agencies. One of the often quoted conceptions was that the monitoring provided a de facto sterility test. This was based upon the knowledge that the compendial sterility test was inherently flawed in its ability to determine product sterility. (Moldenhauer and Sutton, 2004)
The FDA’s Aseptic Processing Guidance (FDA, 2004) provided a significant amount of detail of the requirements of an appropriate environmental monitoring program. Since there were not similar requirements for terminally sterilized products or non-sterile products, many investigators chose to use these rules as applicable to all types of products.
As such, many of the expectations for environmental monitoring are the same for both sterile and non-sterile products. The biggest difference in the two programs is the frequency of monitoring and may have different limits. Sometimes problems occur when limits are set based upon room classifications, e.g., ISO 7 or 8. The problem occurs when some individuals compare the limits in the FDA’s Aseptic Guidance and assume that the microbiological limits described for these room classifications always apply whether you are using an aseptic or non-sterile operation. In fact, there are no microbiological limits established in ISO 14644 Part 1. (ISO, 2015) This document bases cleanroom classifications wholly based upon non-viable particulate levels.
A Total Environmental Monitoring Program
Many people understand that the environmental monitoring program includes media, samples taken from the air and surfaces, getting results, and evaluating the results against existing limits. In reality, this is only a small part of the environmental monitoring program.
Components of a total program should include the following:
- A contamination control program that has deemed the environmental monitoring program necessary and how it should be implemented.
- An environmental monitoring master plan
- An environmental monitoring oversight committee (in some companies this is part of a sterility assurance committee)
- Selected laboratory methods and equipment
o Qualified equipment
o Qualified methods
o Selection of sample sites based upon risk assessment
o Validation/qualification of the incubation and media conditions utilized
- Methods specifically for water, air, compressed gases, surfaces, personnel and clean steam as appropriate
- Conduct of Installation Qualification and Operational Qualification of the manufacturing equipment, at least
- Conduct of the environmental monitoring performance qualification. Many times this may be concurrent with media or water fills. As part of the final report, it is common to adjust or solidify the routine sampling sites to utilize.
- Verification that all operators and technicians are trained and qualified
- Establishment of the routine environmental monitoring program.
- Specified monitoring methods and procedures
- Procedures for Data Collection, Analysis and Trending. This step also includes the establishment of the appropriate limits or levels for the process.
- Trending may include use of automated systems, which are qualified
- Investigation of microbial data deviations (MDD) and resolution of issues
- Identification of contaminants using qualified methods. Maintenance of a library of isolates for your facility
- Conduct of a Product Impact Analysis. For non-sterile products this includes concerns with the FDA Bad Bug List and the Objectionable Organisms listing.
- A corrective and preventative action program (CAPA) that addresses the cause of the excursion and how it was fixed. This should include a check of the effectiveness of the program
This program is depicted in Figure 1.
Where Does Your Program Compare to the Total Program?
Many companies will find that they have several parts of the total program, but others will find several steps missing. Some of the typical steps missing in some programs will be discussed here.
The purpose of the Environmental Monitoring Committee is to ensure that there is a mechanism for ensuring that senior management is notified of environmental trends and actions. It also provides a mechanism to get management support for necessary changes in practices and policies. Ideally, this type of system ensures that “real” corrective actions are achieved. It also is useful in getting financial support for necessary facility or equipment changes needed as a result of monitoring issues. In some companies, where they are making sterile products, this function is incorporated into the sterility assurance committee.
The Microbiology Master Validation Plan is frequently incorporated into a site master plan. More companies are establishing microbiology specific plans with all the details of how methods are selected, qualified and implemented. It also described how equipment is selected, qualified and implemented. It provides an outline of the laboratory’s whole operation.
The environmental monitoring performance qualification may be unique or coordinated with the cleaning and disinfection performance qualification. It involves taking samples in situ, before and after cleaning to evaluate whether the methods and procedures used will result in data that is within limits.
Systems should be established to ensure that the data is appropriately collected, entered and trended. There are several automated systems available to aid in this process. The data should be reviewed in a variety of formats, e.g., where contamination is found in the facility, where specific isolates have been found in the facility, where results are within and outside of established limits, and so forth.
The Microbial Data Deviations (MDD) procedure is a term coined by PDA to address microbial excursions from limits. Since most environmental data is not a specification, this term is better suited than the out-of-specification (OOS) used for most chemistry results. This procedure should require investigations into excursions, risk-based analysis of the results, analysis of the impact of the excursion on the product, and for non-sterile products should include concerns for whether there are specific concerns due to the type of contamination, i.e., objectionable organism. An organism that is always a concern is a member of the Bacillus cereus complex (BCC). These different species of organisms are a concern by FDA for non-sterile aqueous preparations.
The product impact analysis should discuss how decisions were made on the effect of this contaminant on the affected batch(es). Many years ago, a common practice was to say something like, “the product passes sterility and endotoxin testing, so there is no product impact.” These types of generic statements are not typically acceptable. The impact assessment should be a written document that explains the various considerations made, explains the characteristics of the contaminating organisms and why it does or does not impact the product. There are some useful references that may aid in this process, e.g., FDA’s Bad Bug Book available on the FDA website, or Medically Important Fungi.
It is important to think of your environmental monitoring program as a living document, with periodic review and update. This may be yearly or bi-annually. Information that should be considered in these reviews are recent warning letters, regulatory requirements, and presentations. This may be incorporated into procedures that are used to review and revise limits on a periodic basis.
Regulatory expectations and requirements are changing regularly. As such, it is important to look at your environmental monitoring program periodically to assess whether it is consistent with current expectations.
Anonymous (2017) Personal communication of FDA483 inspection reports from clients. These FD483s have not yet been made public on the FDA website.
FDA (2004) Guidance for Industry – Sterile Drug Products Produced by Aseptic Processing – current Good Manufacturing Practice, pharmaceutical cGMPs. Unites States Department of Health and Human Services, Center for Drug Evaluation and Research, Center for Biological Evaluation and Research, and the Office of Regulatory Affairs.
ISO (2015) ISO 14644 – 1:2015. Cleanrooms and Associated Controlled Environments. International Standardisation Organization.
Moldenhauer, J. and Sutton, S.V.W (2004) Towards and Improved Sterility Test. PDA Journal of Science and Technology 58(6):284-286.