New EU GMP Vol.4 Annex I and Environmental Monitoring leverage

by Alessio Rosati, GMP Compliance Advisor & Auditor @PQE Group

New steps to improve your Enviromental Monitoring plan and where they can lead your cleanroom strategy and contamination control

After a long time revision, EU GMP Vol. 4 Annex 1 new version is now about to be issued. This European reference standard for sterile pharmaceutical manufacturing is thus about to change from a light and concise guideline to an improved, highly structured and detailed standard. A lot of new requirements, specifications and recommendations are included in the draft version so far shared by Eudralex, most of which will likely be an important challenge for many sterile manufacturers. Whether you can find more details about EU GMP vol.4 Annex 1 contents in other articles of this website, in this occasion we want to share some considerations and insights of one of the most challenging topics, Environmental Monitoring, and how the impact of Annex 1 guidelines can work as a leverage to get full knowledge and control of manufacturing.

New EU GMP Vol.4 Annex I and Environmental Monitoring leverage - int

Risk-assessment approach: Annex I requirements impacting Environmental Monitoring Plan definition

In the dedicated section, the 2020 draft of the Annex 1 reports an important series of new requirements for Environmental Monitoring, from the design of the sampling plans up to the evaluation of data and results. First of all, a requirement for a mind-set change that is spread throughout all the new Annex 1 document: environmental monitoring plans, whatever they are meant for, must be designed based on a risk assessment approach. This implies that you need to know in deep all the relevant cleanroom areas -how they are designed, used, cleaned, managed and maintained- to strongly identify all the potential criticalities and contamination risks: where may contamination come from? Which are the most exposed areas? Where can the potential contamination sources have a higher impact? The answers to these questions can lead you to design an objective risk-based monitoring plan. And in return, this will allow you to readily and more effectively detect any contamination event or negative drift occurring in your cleanrooms: it’s therefore not only about being in compliance with specifications, it’s rather about getting full knowledge of your environments, to put in place the best detection plan you can design.


New EU GMP Annex 1 requires to evaluate sampling methods and assess contamination risk

Under this perspective, all the parameters composing a monitoring plan are requested to be defined and (possibly) optimized (e.g. number and exact location of the sampling points, and sampling frequency). But there’s more about: New Annex 1 also requires to evaluate your sampling methods, to assess the contamination risk they can pose themselves, and to verify their actual recovery efficacy. So, it’s not only about deciding where and when to monitor, but also how and with what expected results or data. Again, it is about getting full knowledge and understanding of what you’re doing, how and why.


Data Trending: quality of environment monitoring data giving in-depth insights on contamination and alert limits

Another important aspect arising from the text of the new Annex 1 is data trending. Every sterile manufacturer knows that monitoring activities generate a huge amount of data. Firstly, following what we’ve so far said, it is important to improve the quality rather than the quantity of EM data: a risk-based monitoring plan will provide you data from the right places and the right times. And consequently, it is important to know what to do with all these data! Evaluating EM data requires a critical approach, deep microbiology knowledge and specific statistical tools, but they can be an important resource of information regarding:

  • the microflora present in your cleanrooms;
  • source, routes and dynamics of contamination;
  • the actual efficacy of the contamination containment strategies you put in place: from cleaning and disinfection, to materials management zoning design, barrier technologies and personnel behaviour.

A dedicated statistical analysis can also provide you another important tool for your cleanroom control activities: alert limits (AL). The new revision of EU GMP Annex 1 requires alert limits to be calculated based on historical data. This approach, if supported by the right statistical approach, allows the design of the most appropriate alert limits: when they are tailored at the actual bioburden levels of your cleanrooms, they can become an important tool to readily detect incoming spikes and negative drifts. Of course, it needs you to master specific statistics knowledge, but otherwise, if you set alert limits using the wrong statistical approach, or no statistical approach at all, you’ll most likely have to face two alternative scenarios, the former more time and effort wasting than the latter: on one hand a high amount of useless false positives (when the alert limits are mistakenly set too low), on the other hand detecting negative drifts and issues when it’s too late (if the limits are set too high).



In the end, we can say that yes, the new Annex 1 contains a lot of new and challenging requirements regarding the environmental monitoring of sterile manufacturing areas. But it’s also true that if integrated with the right mind-set and approach, with the adequate knowledge and skills, they can bring you to set a brand new monitoring strategy, more robust, more informative, and hence much more useful!

Any Issue with Sterile Manufacturing?

PQE Group staff comprises experienced and skilled experts that can support you in the goal for compliance with the new arriving Annex 1, in every aspect of your aseptic manufacturing: sterility assurance strategies, quality compliance, microbial monitoring, cleanroom design and revamping, equipment qualification, critical system validation, analytical methods selection and validation, and many others.
Check out Compliance Services, and contact our team to request a meeting with our experts.


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