Since 2017, Annex 1 Manufacture of Sterile Medicinal Products of EU GMP Volume 4 has been undergoing significant revision. In August 2022, the revisions were finally completed, and will become coming into operation in August 2023. But how do these changes change things? Microgenetics' Edward Webber explains
Annex 1 was introduced to prevent contamination in the final product. The updates include many clarifications and additional instructions for sterile manufacturers to consider, from pharmaceutical quality systems and guidance for using Quality Risk Management (QRM) principles to the concept of a contamination control strategy.
One significant aspect of the contamination control strategy is the environmental monitoring programme. Annex 1 requires a written sampling plan for your environmental monitoring, and that your contamination control strategy should directly influence your EM programme. This plan should provide you with meaningful data, providing assurance that cleanrooms are appropriately clean and that you are able to detect excursions which may provide a risk to product quality.
You need to know the most likely sources of contamination, as well as where the highest risk areas are
This data therefore requires regular review to make sure your manufacturing environments remain under control. Annex 1 states that the environmental monitoring programme should form a part of your overall contamination strategy and should monitor the controls you have in place to minimise contamination.
Annex 1 gives clear instruction about certain considerations which should be given in your environmental monitoring programme. The programme should, according to the guidance, contain the following elements:
It explains what factors should be assessed in your risk assessment. These include:
Information from your environmental monitoring programme should be used for release of product, but also for ongoing assessment of the conditions of your cleanrooms, and during investigations. You must base your risk assessments on knowledge of your processes, as well as historical monitoring data, qualification monitoring data and the facility itself.
It’s therefore a requirement to fully understand each of your processes when writing your contamination control strategy and environmental monitoring programme. You need to know the most likely sources of contamination, as well as where the highest risk areas are.
High risk includes both the areas most likely to introduce contamination to the final product, but also the areas which have the highest risk of introducing contamination, such as those with poor airflow, or where contamination could be tracked into your cleanest areas.
If you understand all of this, then it gives you a much greater chance of preventing contamination, but also gives you a greater chance of catching when this contamination occurs through thorough monitoring of the highest risk areas.
Your environmental monitoring programme is designed to prevent contamination of your product. You need to monitor your facility to ensure it is clean and that you are unlikely to introduce contamination into your product. It is important to make sure you perform monitoring in positions which have been selected and justified using your risk assessment process, with the highest risk areas being monitored the most frequently.
Grade A environments: The new revision of Annex 1 emphasises the importance of continuous monitoring during processing. This allows you to be sure that no viable or total particle contamination is present in your grade A areas throughout the manufacturing process and gives additional confidence in sterility.
The latest revision of Annex 1 also provides clarification when it comes to Grade A limits. Whereas previously, it was stated that there should be less than 1 CFU, it now states that the target for your cleanest area is zero. This means you need to monitor these areas in such a way to ensure you are recovering no organisms in your grade A environment.
Other grade environments: Annex 1 states that the Grade B areas require monitoring at a frequency which will allow you to detect increases in contamination or system deterioration, as well as capturing when alert or action limits are breached.
The new revision of Annex 1 emphasises the importance of continuous monitoring
It is also important to consider other characteristics such as temperature, relative humidity, and airflow in your environmental monitoring programme. These should all be controlled to make sure you are able to manufacture your product safely and maintain cleanliness during manufacture. Airflow patterns should also be examined, using air visualisation studies that are conducted during qualification, and the outcome of these studies should be reviewed as well.
Annex 1 also highlights the importance of monitoring the total particle levels within your cleanroom. The alert and action limits are specified in the Annex; however, it also states that more stringent limits may be applied depending on your data trending and historical data. There are also no set limits for operation monitoring of total particles in grade D areas, as it is the manufacturer’s responsibility to establish these limits based on routine data.
One of the most common sources of contamination is the operators within a cleanroom, and the final revision of Annex 1 has added a whole new section about personnel monitoring – monitoring occurring following involvement of operators in critical interventions.
Operators in grade A and B areas should be monitored for microbial contamination to determine whether they are likely to have introduced any contamination into the critical areas. At a minimum, they should have gloves monitored. Gown monitoring may be required if the processes being performed may lead to contamination being transferred from the gown to the critical areas.
Operators involved in manual operations have an increased risk of microbial contamination to the product, and therefore increased microbial monitoring should be performed on these operators and their gowns.
Materials and equipment are also a possible source of contamination. Items should be sterilised prior to entry into the cleanest areas; however, Annex 1 recognises that it’s not always possible to perform sterilisation on some of these items. It, therefore, instructs that these should be disinfected and transferred safely into the clean areas, and these items and disinfection processes should be included in the environmental monitoring programme.
Annex 1 also highlights the importance of your environmental monitoring programme taking into consideration factors like your air filter configuration, air filter and cooling systems integrity, and your equipment design and qualification.
These factors can all influence your contamination control, and therefore your monitoring should consider changes in airflow, temperature, and system integrity.
Now that the final revision of Annex 1 has been released, it is important to review your environmental monitoring programme to make sure the methods being used are still compliant.
You should begin with a full audit of your EM processes, understanding which methods you are currently using, why you are using them, and what sort of data is being produced. You need to understand this to make sure that you are compliant with the released revision, especially with the newest sections such as the utilities section, which has information detailing equipment and other materials which may encounter your product.
It’s important to make sure you are looking at both viable and total particle contamination, pressure differentials, temperature and humidity, and airflow.
Annex 1 recognises that it’s not always possible to perform sterilisation on some items
This data is all trying to provide you with insight into the aseptic condition of your manufacturing facilities, and allow you to evaluate your processes, so it is important to make sure you have complete data. You should consider how well your current systems work for this, and how well they will detect when you have contamination.
When documenting your new environmental monitoring programme, you must consider all areas of your operations, from initial manufacture of raw materials and components to the final product filling and finishing procedures. Monitoring of surfaces, air (using passive and active air sampling), compressed gasses and personnel should be documented, and you should understand the consequences of non-compliance.
It’s important to understand how well your containment strategies are working. Your environmental monitoring programme should therefore include consideration of results generated from your environmental monitoring. This includes trend analysis of your results, analysis of organisms recovered in your facility, and an understanding of the source and routes of contamination.
All environmental monitoring data for your classified areas in your cleanrooms should be reviewed as part of batch certification, but also reviewed regularly outside of manufacture to confirm control.
Within your environmental monitoring programme, you should document the actions which should be taken if any limits are exceeded, or emerging trends are detected. If action limits are exceeded, or trends are identified, then root cause investigations should be performed, and an assessment of the potential impact to the product should be performed.
Corrective/preventative actions should also be detailed. It is important to perform an investigation on the impact of any batch produced between the monitoring and reporting, not just the batches manufactured during monitoring. If alert limits are exceeded, assessment and follow-up should be documented, and this should consider whether additional investigation or corrective/preventative actions may be required to prevent further deterioration of the environment.
Annex 1 states that “particular attention should be given to organisms recovered that may indicate a loss of control, deterioration in cleanliness or organisms that may be difficult to control”. This means that, as well as performing identification from any isolates in your Grade A and B monitoring, periodic review of isolates recovered in your grade C and D areas should also be performed. An idea of the “normal” flora in these areas will allow you to then detect if any changes to this norm are occurring.
You also need to review your environmental monitoring programme to make sure you are getting useful and accurate data, and make sure any new changes in regulation are captured as well. Updates may be required to drive continuous improvement to the manufacturing and control methods, and its effectiveness should be assessed periodically.
Now that Annex 1 has finally been updated and released, it is now more important than ever to make sure you have a well-documented environmental monitoring programme. You need to understand how your current monitoring systems can be updated to meet these requirements, and you need to produce data which can be analysed and understood. Of course, all of this emphasises the need to understand your processes and your data, not only where and when monitoring is required, but also what the results mean.
You should review and streamline your environmental monitoring programme periodically to make sure you are minimising risk to your products, so you should understand your processes and what the data means to effectively control these risks.