Introduction

The revised Annex 1 /1/ was published in August 2022 with 1 year for implementation, which means that the industry needs to be compliant within August 2023. So, what are the major changes and challenges?

QRM and CCS

These two terms are truly the most important things in the new Annex 1. QRM means Quality Risk management and highlights how all decisions should be determined based on the actual risk. Guidance to QRM may be found in ICH Q9 /2/.

The term CCS is mentioned not less than 59 times - in 59 pages!  CCS means Contamination Control Strategy and should be a complete overview of the measures taken to ‘control’ contamination in all steps from raw material to delivery. The CCS may be written as a matrix or as a text document. For complex production plants, the CCS preferably may be split into one main CCS and several sub-CCSs to cover the details and references to applicable procedures.

Premises

There are not many new requirements for premises, but an important point to remember is the separation of personnel and material flows. The need for barriers should be determined in the CCS, and the material flow in and out should be clearly divided in space - or if necessary - in time. This means, the premises should provide separate hatches for materials in and out, and respectively for people in and out.

Furthermore, the use of smoke visualization is highly recommended, both to document the air velocities "at rest" and "in operation", but also as a tool for verifying where there is the highest contamination risk. According to the visualization results, the CCS should justify the amount and location of the settle plates for monitoring.

Isolators and RABS

The use of closed spaces for zone A is now clarified, and there should be a very good reason for not using an isolator or RABS in these cases. When using those closed containers, they should be equipped with the possibility for continuous particle measurement and for vapour decontamination e.g. with hydrogen peroxide.

Qualification versus monitoring

The new Annex 1 has adopted the ISO 14644-1 view on ‘classification’ of ISO 5 for particles ≥ 5µm.  For grade A and B ‘at rest’ and grade A ‘in operation’ they have been indicated as ‘Not specified’ unless indicated by the CCS or historical trends.

For monitoring, the number of particles ≥ 5µm are limited, although the limits for grade A are now in line with the ISO 14644-1 classification table, which was previously not the case.

Monitoring

Whether the requirement of 0 cfu in a class A environment is new or not, depends on how the manufacturer has read and understood the previous requirement of "less than 1" cfu/m³ in class A environment. However, now there should be no doubt about that. Following this strict requirement, the measures taken by a positive test should be clearly defined and include a root cause investigation. There should also be a more overall approach to all the findings, combining vial and non-vial contamination, and a library of the common findings should be established.

Nevertheless, the monitoring program should be justified from the QRM and based on the manufacturers CCS.

Training and knowledge

There are now higher expectations to training of personnel. They should have a basic knowledge of how people influence the total contamination level in cleanrooms, which means microbiology, hygiene, clothing, behaviour etc. The main difference from the previous revision is that people are expected not only to know HOW – but also know WHY – they should behave and follow the specific procedures.

Product specific technologies

Here you can find guidance about aseptic processes and processes with terminal sterilization processes. There are both general requirements, and specific requirements directly related to specific technologies, e.g freezedrying and form-fill-seal.    

How to become compliant?

After reading the new Annex 1, the most common question is: How can we become compliant?

The first step should be to establish both a QRM and a CCS. When those frameworks are established, one can see what existing measures are already in place. The second step will then be to realize what is missing – and must be achieved. This second step could be seen as a GAP-analysis.

Figure 1 "Closing the GAP"

For smaller manufacturers, this process could – if necessary – be a good opportunity to make sure the senior management understands the consequences of the requirements in Annex 1.

References:

/1/         https://health.ec.europa.eu/system/files/2022-08/20220825_gmp-an1_en_0.pdf

/2/         https://database.ich.org/sites/default/files/ICH_Q9%28R1%29_Guideline_Step4_2023_0126_0.pdf