Annex 1 – Can we all take a deep breath now?

The impending enforcement of EU GMP Annex 1 should not bring forth any more industrywide anxiety, but rather, let it be a relief from the constant barrage of stress-inducing messages about readiness and compliance (although I doubt they will let up).

The principles outlined in the Annex 1 guidance document are not new or novel to the pharmaceutical industry, and I would even highlight that most of the content was known prior to its release in 2022. In the United States, we have had several documents that prescribed the same or similar concepts for contamination control, sterility assurance and other key topics focused on facilities, equipment, personnel, new technology, and methods.

Sterile drug manufacturing is an industry that has always exercised much caution, has moved towards quality by design, implemented risk management strategies, and even in the past decade has definitely improved the way in which potential contamination is mitigated. The paradigm has shifted towards being proactive rather than reactive, and from a microbiological perspective, this means consciously preventing contamination before it would ever need to be detected and quantified downstream.

The 2022 Annex 1 revision formalizes the creation and implementation of a contamination control strategy as the founding principle for its guidance and the manufacturing of sterile drug products. Annex 1 also provides more specific details with respect to the CCS in each of the subsections of the regulation, applying their principles and demonstrating how they are connected to each other for aseptic processing.

The key to demonstrating compliance for this document is to show your initial strategy, and then how it’s interconnected to each aspect of the business in everyday management of your process. If you have been operating in the regulated industry as all other sterile manufacturers have, then you should have had most or all of the elements of a contamination control strategy. Pulling them together, and making sure that they are functioning as intended, is the consolidated compliance ask from Annex 1.

This is no different than defining the parameters for any other major program, and in fact, if you already have a Sterility Assurance group, then I would wager you likely had the principles outlined in Annex 1 in one way or another. If you did not, or you are the type of business that waits until it’s forced to be compliant, then you probably have a whole other host of business concerns too. Either way, time is up. 

If time waits for no market, then here is my short and sweet list of topics to ensure Annex 1 compliance (no, this is not exhaustive):

  • Use the best technology (available to your process) to protect the product
  • Have a contamination control strategy, but also a plan to demonstrate its proper execution
  • Make sure employees are genuinely educated and trained in practical sterility assurance and microbiology concepts/techniques when entering the aseptic areas
  • Employ PUPSIT where the process permits and justify when it does not
  • Design the Aseptic Process and its simulation with zero contamination as the target
  • Make use of rapid, alternative and/or automated QC testing methods when possible
  • Ensure everyone is responsible for process knowledge and sterility assurance 

Remember, if you are checking off this list or copy/pasting language from the guidance into your procedures, then you are missing the entire point. Establishing compliance and implementing sterility assurance principles is much more than a paper exercise in every sense of the act. 

Vanessa Vasadi Figueroa is the QxP Executive Director of Microbiology & Sterility Assurance. During her almost 20 years in pharma quality, Vanessa has built a reputation for her deep knowledge of microbiology and contamination control. Vanessa was one of the co-creators of the QxP Virtuosi learning platform.

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