Reducing Risk in Your Environmental Monitoring Program

The goal and commitment of every pharmaceutical manufacturer is to produce a quality product that is safe and effective for patients. Environmental monitoring (EM) plays a significant role in achieving this goal as it provides critical information about the manufacturing environment in order to prevent the release of a potentially contaminated product.

Given the importance of environmental monitoring, there are many regulatory requirements and guidances available surrounding EM activities. The standards, like the EU’s Annex 1 GMP guideline, are continuing to change and are becoming stricter and more rigorous. It is important to remember that even though EM functions are usually performed by the microbiology laboratory, they are closely tied to the Quality department. As such, the principles of Quality Risk Management still apply, and it is imperative to identify where risk can be reduced. By reducing risk associated with an EM program, your regulatory position is strengthened, the quality of the product can be improved, and patient safety is assured.

Risk management is particularly important in regard to current and future regulations, data trending, and data integrity as related to surface and air sampling, personnel monitoring, bioburden counts, and microbial identifications.

Proposed Revisions to Annex 1

It’s been over two years since the EU announced revisions to Annex 1 of the EU Good Manufacturing Practice (GMP) guideline for the “Manufacture of Sterile Medicinal Products.” This is a central guidance document that applies not only to EU drug manufacturers, but any global drug manufacturer with customers in the EU. Even more important, the scope of Annex 1 includes “principles and guidance, such as contamination control strategy, [and] monitoring…[that] may be used to support the manufacture of other products that are not intended to be sterile (such as certain liquids, creams, ointments and low bioburden biological intermediates) but where the control of microbial, particulate and pyrogen contamination, to reduce it as far as possible, is considered important.”¹ Thus, even though Annex 1 may initially be considered a strictly European document, it applies to the vast majority of pharmaceutical manufacturers and provides sound guidance for all EM and contamination control strategies.

A key emphasis in the proposed draft of Annex 1² is the incorporation of Quality Risk Management (QRM) to all manufacturing functions, including environmental monitoring. It starts in the very beginning when facilities and cleanrooms are being designed. “Processes and monitoring systems for sterile product manufacture must be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge” (lines 40-42).¹ This ensures that not only the process flow, equipment, and materials are appropriate for the manufacturing operation, but that sanitation and sampling needs are considered as well. Companies are expected to conduct a comprehensive assessment of the design and control of manufacturing operations with a detailed and thorough review of all microbiological hazards. This risk assessment is not intended to be a one-time activity but should be regularly reviewed.

Moreover, periodic review is expected of an established EM program for its effectiveness at detecting contamination (line 794).¹ This is by no means a small task, but often overlooked. Some suggested questions to continuously consider:

• Are there any new risks associated with my EM program?
• Is my EM program fully capable of detecting contamination? Are there new areas for microbial ingress?
• Have there been changes made to the EM program and do they introduce any new risk?
• Are my EM methods modern and scientifically sound? Are there new developments or improvements that would be beneficial to implement?
• Is my sampling plan reflective of current manufacturing operations and procedures?
• Is my EM program guided by accurate, scientific microbiological principles?
• Am I reviewing my EM data in a way that is meaningful? Is the frequency of my review appropriate?

Any risk to an EM program means added risk to the final product. Annex 1 sets the expectation for the “assessment of the… introduction of scientifically sound, modern methods that optimize the detection of environmental contamination” and …continuous improvement based on information from the above [monitoring] systems” (99-102, 105).¹ Accurate data and microbial identifications allow you to make operational decisions with appropriate justification.

Trending Data

While so much time and labor are devoted to generating and gathering EM data, oftentimes it then gets simply filed away or stored in a spreadsheet. For a truly comprehensive and reliable environmental monitoring program, tracking and trending counts and microbial identifications are a critical piece to understanding the manufacturing environment. Any changes to counts or flora indicate a change to the environment, which could indicate risk to manufacturing processes and products. This is emphasized in section 10.10 of the revised Annex 1. “Environmental monitoring data generated in grade A and B areas should be reviewed as part of product batch release. A written plan should be available that describes the actions to be taken when data from environmental monitoring are found out of trend or out of specification.”

Moreover, microbial identifications should be performed to the species level. This allows for more effective trending and provides more meaningful data. By knowing when and where this organism was seen, it can provide insights into how that organism entered the facility and how to remediate it. Also, knowing the actual species allows more relevant risk assessment on how that organism can impact manufacturing processes, final products, and potential patients.

For example, consider a pharmaceutical company that saw an increase in Bacillus counts. What does this mean for their final product? As Bacillus are common spore formers, is the product adequately sterilized or preserved from spores? Is the cleaning and sanitation program appropriate for removing spores? By trending the flora, this company found that Bacillus spiked every fall, and they were able to trace it back to their HVAC systems. They were located in a rural environment and the increased recovery correlated to when local farms were harvesting crops and disrupting the soil. The company mitigated the contamination by changing their HVAC systems and HEPA filters, as well as increasing the use of sporicides.

As previously mentioned, trending of data is a regulatory expectation. The word “trend” was never used in the 2008 version of Annex 1; however, in the 2017 revision, “trend” appears 16 times. Section 9.32 in Annex 1 states that: “Monitoring procedures should define the approach to trending. Trends can include but are not limited to:

1. Increasing numbers of action or alert limit breaches.
2. Consecutive breaches or alert limits.
3. Regular but isolated breaches of limits that may have a common cause, for example single excursions that always follow planned preventative maintenance.
4. Changes in flora type and numbers.”

The FDA expectations are the same, as evidenced by numerous warning letters. In a recent letter, a company was cited they “did not thoroughly investigate negative environmental trends.”³ Although EM data is not in real time, your EM program is designed as an early warning surveillance system.

Any excursions or negative trends are meant to be evaluated. Indeed, the same company was also cited as the “risks posed by the potentially valid contamination findings and related impact were not sufficiently addressed.”³ It is not enough to just review the data; action should be taken to remediate or prevent contamination. Environmental trends warrant a review of the existing manufacturing controls.

Data Integrity

Sound data analysis can only be conducted when the data is accurate and reliable. Without quality data, trending can be inaccurate and any conclusions or remediations may be ineffective. The data can lose its value and meaning. This has been recognized by the regulatory agencies and there has been a significant push over the last few years for adoption of data integrity practices.

Environmental Monitoring of pharmaceutical manufacturing facilities is critical for regulators, including accurate microbial identification.

Data integrity is defined as “the maintenance of, and the assurance of the accuracy and consistency of, data over its entire lifecycle, and is a critical aspect to the design, implementation, and usage of any system which stores, processes, or retrieves data.”4 In their FDA’s “Data Integrity and Compliance with Drug CGMP Questions and Answers, Guidance for Industry,” the organization clearly states that they “expect that all data be reliable and accurate.”⁵ They go on to emphasize that “ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs.”⁵

Besides accuracy, the other foundational aspects of data integrity can be found in the ALCOA+ acronym: Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available. The enforcement of data integrity regulations can be evidenced in many FDA warning letters. “A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.”³

Data integrity in the microbiology laboratory has unique challenges, and it may be easier to think about it in terms of reducing human error. For example, a core function of QC micro is to count bioburden and sampling plates. As these are live organisms on agar plates, how do we ensure the count is accurate and what do we consider as the raw data? Some companies respond to these considerations by photographing the plates and using the “four-eye” principle to authenticate the original count. Other companies are moving to automated count readers where the data is validated and stored electronically. Other examples include phenotypic microbial identification systems, where biochemical and metabolic tests are read based on color change or turbidity, and endotoxin gel clot assays. These results are subjective, as different technicians may read the tests different ways. This creates a problem with accuracy and reproducibility, which is troubling when product is being released based on these test results. Hence, it is clearly important that all microbiology lab functions are evaluated for data integrity compliance.

The importance of data integrity is reiterated in another FDA warning letter: “Your firm did not maintain complete and accurate data from all laboratory testing. Without reliable laboratory data, you cannot assure appropriate decisions regarding batch release, product stability, and other drug aspects of quality.”⁶ Because environmental monitoring establishes the state of control of the manufacturing environment and is critical for product release, it is imperative that the QC microbiology laboratory performs tests accurately, reliably, and timely.

Conclusions

Government regulations for the manufacture of pharmaceutical products are intended to protect the public by ensuring safe and effective products for patients. It may feel like the rules are too rigorous or it is too challenging to keep up with changes, but they are necessary. Patients are counting on them, now more than ever. With COVID-19 sweeping across the globe, demand for pharmaceutical products is high. As manufacturers are adjusting their operations and many are short-staffed, we need to stay committed to best practices and contamination control.

It is well recognized that final product testing on just a small subset of a production batch is not a complete picture of whether the entire batch is contamination-free. Thus, environmental monitoring is just one way to reduce risk by detecting possible contamination throughout the manufacturing process. Evaluating the effectiveness and integrity of your EM program on a routine basis is essential, as well as trending your EM data to look for areas that can be better controlled. In the end, this results in better compliance, increased quality, and improved patient safety.

References

1. European Commission. “Annex 1 Consultation Document.” 20 December 2017. https://ec.europa.eu/health/sites/health/files/files/gmp/2017_12_pc_annex1_consultation_document.pdf
2. BioPhorum. “Microbial control: Risk assessment of traditional culture-based microbiological tests requiring contemporaneous verification.” April 2020. https://www.biophorum.com/download/risk-assessment-of-traditional-culture-based-microbiologicaltests-requiring-contemporaneous-verification-april-2020/
3. US Food and Drug Administration. “FDA Warning Letters.” Accessed 19 April 2020. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warningletters/pfizer-healthcare-india-private-limited-594972-03252020
4. J. Boritz, International Journal of Accounting Information Systems (Elsevier, Archived from the original on 5 Oct. 5, 2011). Accessed July 9, 2019.
5. FDA, Data Integrity and Compliance with Drug CGMP Questions and Answers, Guidance for Industry, (FDA, December 2018), www.fda.gov/media/119267/ download.
6. US Food and Drug Administration. “FDA Warning Letters.” Accessed 19 April 2020. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warningletters/windlas-healthcare-private-limited-595494-03102020