USP 1116: Points to Consider and the Role of Rapid Methods

At a recent PDA workshop on the revised USP Chapter 1116, Microbiological Evaluation of Clean Rooms and Other Controlled Environments, a number of speakers provided an overview of the changes but more importantly, the regulatory perspectives on the new informational monograph. With the introduction of real-time rapid microbiological method (RMM) technologies that are intended to detect, size and enumerate both total particulates and viable microorganisms in air, USP 1116 may be a welcome change, as these RMM’s are capable of continuous monitoring, single cell detection and enhanced trending of environmental monitoring (EM) data. Obviously, the ability of these systems to continuously trend non-zero results, especially in an ISO 5 or Grade A environment, may be worthwhile to the industry, and is relevant to the teachings of USP 1116.

One of the speakers at the workshop, Dr. David Hussong, Associate Director for New Drug Microbiology at FDA/CDER, stated that random detectable counts are to be expected even in the most controlled manufacturing areas, especially from operators, equipment, and possibly other sources. However, any excursions from expected EM specifications or acceptable levels are considered deviations that indicate a problem. Furthermore, operational data should establish a normal or expected baseline, and when low level or infrequent counts are expected, charting or trending of the data will certainly help to understand the overall control of the area over time. For example, this would help to visually demonstrate that three positive “hits” over three days is a worse trend than three positive “hits” over a month. This is where USP 1116 can come into play.

Dr. Hussong explained that the purpose of the new USP chapter is to deal with low numbers of recovery in cleanrooms. USP 1116 allows to trend and demonstrate process control, and to satisfy regulatory requirements that demonstrate process control, in addition to signaling operators when the process drifts away from established control parameters; however, it should be understood that the methods and acceptance criteria are to be established for each facility’s needs. Dr. Hussong stated that EM data:

• Are NOT product release criteria
• Are useful, but should be weighed against risks associated with the operations (e.g., a higher number of personnel or more manipulations)
• Are needed to understand process control for aseptic filling operations, terminally sterilized product lines and non-sterile manufacturing
• Should provide suitable alert and action level responses, and that excursions should have appropriately graded responses which are not necessarily an indication of an out-of-specification (OOS) finding

I had the opportunity to ask Dr. Hussong how the FDA views USP 1116 in light of existing regulatory expectations for using specific control levels for EM within controlled and classified manufacturing areas. Here is a brief summary of the Q&A exchange.

Q: Does the FDA currently expect firms to continue to meet existing levels for EM as specified in FDA’s aseptic processing guidance for industry?
A: Yes.

Q: Would this be applicable for all classified areas, including ISO 7 and 8?
A. Yes.

Q: Will the FDA allow companies to move toward trending (as described in USP 1116) and completely abolish the quantitative action/alert levels for EM?
A. Yes, but only with data to support this change.

Q. You represent the Review side of CDER. Does the Compliance side of CDER also accept the recommendations provided in USP 1116?
A. Grudgingly they do, but there are ongoing discussions between both sides.

Personally, I believe that trending in our cleanroom and controlled areas provides a more realistic understanding of environmental process control, and by implementing the continuous and real-time monitoring capabilities of laser induced fluorescence RMMs will help the industry in meeting the spirit of USP 1116. However, I caution the reader of this blog that the teachings of USP 1116 may not be widely accepted by all regulators, especially outside of the U.S. Additionally, there are some statements within the chapter that the industry should consider very carefully before implementing all of the recommendations as provided in USP 1116.

For example, USP 1116 states that “Excursions beyond approximately 15 cfu recovered from a single ISO 5 sample, whether from airborne, surface, or personnel sources, should happen very infrequently. When such ISO 5 excursions do occur, they may be indicative of a significant loss of control when they occur within the ISO 5 critical zone in close proximity to product and components. Thus, any ISO 5 excursion >15 cfu should prompt a careful and thorough investigation.” In all honesty, it is unclear to me how a level of 15 cfu was chosen to represent a loss of control in a critical manufacturing area. Why wouldn’t a level of 12, 10 or even 8 cfu be considered as indicative of loss of microbial control, especially when these levels are observed in a critical location? A very recent discussion I have had with a European regulator on this very subject confirms my notion that the chapter suggestions may not be universally accepted.

Therefore, firms should review and understand all of the chapter recommendations and their potential quality and regulatory impact(s) prior to removing their EM specifications or levels, and to include a trending strategy, in addition to their current methods, in order to accumulate the necessary data and scientific evidence that could allow them to follow the essence of USP 1116 at some point in the future.