The new EU GMP Annex 1 was approved in August 2022 after a very long period of discussions. People can expect that regulatory innovations are a step forward in quality assurance of medicinal products. But is it really so?
We have observed an explosion of seminars and conferences that describe changes to Annex 1 without explaining them in depth. Thus, we can see huge confusion in Annex 1 regarding its requirements for cleanrooms. It is a pity that those who made the changes ignored investigations and submissions by the PDA to the EU GMP Commission.
Let’s look if the changes are positive or if they have no sense and even jeopardise quality of products. There are several points to consider regarding this:
- cleanroom classification vs monitoring
- mandatory doors interlocking and safety issues
- RABS and isolators
- others
Tables for particle concentrations
Airborne particle concentration limits were a subject of several changes in previous editions of Annex 1. The new Annex 1 makes more changes and even separates limits for classification and monitoring (Tables 1 and 5).
These tables pose interesting questions.
Limits for particles ≥ 5.0 μm
This problem was discussed in the author’s article in “Cleanroom Technology” not so long ago. The article shows that there is absolutely no sense in controlling airborne particle concentration with both sizes ≥ 0.5 μm and ≥ 5.0 μm for several reasons.
MPPS point and filter efficiency: Air filter efficiency depends on particle sizes dramatically because of the MPPS (Most Particles Penetrating Size) feature. This MPPS point is somewhat between 0.3 and 0.5 μm for HEPA filters. So particles of 0.5 μm represent the worst case (from 0.5 and 5.0 options) because of the lowest filter efficiency at 0.5 μm. For bigger particle filtration, efficiency grows rapidly. For ≥5.0 µm particles it exceeds by many orders of magnitude. So if the filter passes the 0.5 μm limit then it will pass 5.0 μm limit with a great redundancy and the danger of 5.0 μm particles is negligible.
The importance of such events was not observed in real practice and can be considered as an arbitrary office opinion
This filter’s feature was soundly explained in EN 1822-1 standard in 1990 [3]. That is why it was not clearly understood by the wide public in 1980 when the EU GMP requirements for cleanrooms appeared.
So what was forgivable then is not forgivable now.
US and EU differences: US FDA and EU for particle sizes requirements differ:
- EU sets the limits for both ≥0.5 and ≥ 5.0 μm particle size but
- FDA sets ≥ 0.5 limit only
Does this mean US drugs are worse the European ones? Can anybody present even a single piece of evidence to prove this version? No! There is no evidence! This could have been a subject of discussion in 1980 when the US and EU GMP norms appeared, but now, after 40 years of experience, this subject is absent.
It is time to say clearly that the ≥ 5.0 μm limit is a dogma that should be eliminated.
Some people say that ≥ 5.0 μm particles may carry microorganisms, so their control helps to provide microbiological cleanliness. Another opinion is that people emit big particles that can deposit on a product avoiding exhaust from a cleanroom and further filtration (in the case of air recirculation).
However, the importance of such events was not observed in real practice and can be considered as an arbitrary office opinion.
Critical and non-critical zones
There is no sense in testing 5.0 μm particles. But if you are to do this, a respect to fundamental principles is mandatory. We see a confusion here again.
Concentration limits for particles ≥ 5.0 μm/m3 are specified for grades C and D and are not specified for grades A and B. So critical zones with grades A and B may not be controlled, but zones of secondary importance C and D shall be controlled.
This is a violence of common sense and real practice: requirements for critical zones shall be more severe than for secondary importance zones. What about care on quality and common sense?
29 particles ≥ 5.0 μm limit: The limit of 1 particle 5.0 μm/m3 existed until 2008. Then it was changed to 20 particles for grade A and 29 for grade B. This was the consequence of harmonisation of Annex 1 with ISO 14644-1 standard without understanding the matter. Annex 1-2022 became even weaker establishing 29 particle limit both for grades A and B. But this is 1-2 orders of magnitude weaker than in Annex 1 before 2007!
Simple unreasoned changes in location of symbols and parameters can create mix-ups in the field
It is important to note that the old limit of 1 particle ≥ 5.0 μm/m3 of air was achieved 30+ years ago for “good cleanrooms”. There is no reason to make the limit weaker. Maybe somebody advocates this weaker limit in favour of “bad cleanrooms”, but this argument should be excluded especially for sterile production. Quality is paramount for medicinal products. For this high quality of norms is mandatory! Annex 1 moves in the opposite direction as we can see. What about responsibility? Can society trust the authorities that approve such norms?
Particle counting problems: 5.0 μm particles created severe problems with cleanroom classification and monitoring because of air sample volume (statistics issue) and big particles deposition on tubes. These problems are for nothing and will be eliminated with the withdrawal of 5.0 μm limits
Forms of Tables: The new Annex offers different forms for Tables than earlier ones. Before 2022, occupancy states were in the second line of the Table and threshold sizes were in the third. Now we see the opposite picture: threshold sizes are in the second line and occupancy states are in the third. Simple unreasoned changes in location of symbols and parameters can create mix-ups in the field. They increase risks in the most unreliable and sensitive sector – people.
Start-up testing vs Routine monitoring
Annex 1 separates requirements for start-up and routine monitoring and it is done in a very interesting way. Annex 1 makes a step forward regarding ≥ 5.0 µm particles in some senses. It cancelled these particles from classification (start-up) testing for grades A and B, but, at the same time, it retains monitoring of particles ≥ 5.0 µm for routine control. Thus, the new Annex specifies a more detailed and rigorous routine control than start-up testing.
A fundamental rule says (Figure 1): “A scope of start-up testing shall be always bigger (wider) than for routine monitoring”. Otherwise, a fault can be overlooked at start-up and found at routing control only. Table 5 of Annex 1 breaches this rule.
In principle, there may be a situation when a dangerous defect could remain hidden because of missing tests at start-up. But this defect will be found at routing control. Resolving the situation may require changes of design and the facility will be in an unhappy situation.
Doors Interlocking
The previous Annex 1 allowed both an “interlocking system or a visual and/or audible warning system to prevent the opening of more than one door at a time.” Now the Annex requests “doors interlocking” as mandatory. But this is a huge safety violation for personnel where safety should be a priority. This may lead to some dangerous situations provided below.
Situation 1: A person cannot leave a cleanroom in an emergency if an interlocking system is faulty. A person will essentially be in a “mouse trap.” An alarm situation is unusual for people who can easily fall into a panic and escape actions must be accomplished quickly and encounter no barriers, such as may be posed by doors interlocking.
Situation 2: This is opposite to situation 1. There is no emergency case, but only a single person is present in the room. He or she may feel sick, open the inner door of an airlock and fall faint. Because the outer door is interlocked, a sufficient amount of time is needed to resolve the situation. This necessary time can exceed what is needed to save the person. This scenario reflects a real case at one factory and suggests that there should be no mandatory door interlocking.
Scientific justifying
Annex 1, item 4.1, says that “Controls and monitoring should be scientifically justified and should effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches”.
There are some noteworthy comments on this:
- How to distinguish “scientific justifying” from a “non-scientific one”?
- What does it mean to order the investigation from a company/person who impersonates a scientist?
- Why are they better than professionals at the manufacturing company who know their process equipment, but not considered to be scientific?
- How to distinguish “effective evaluation” from “evaluation according standards” and who proves the “effectiveness”?
This play on words probably results from lobbing of interests of numerous consultants to create income by approval of such “regulations”.
This play on words is dangerous. It can replace thorough, really useful and not “scientific” engineering work by the next circle of pseudo-GMPs that are known as “Great Mounts of Paper”. To replace a real worker with a person in “scientific” dress is not good practice.
RABS and isolators
Annex 1 item 4.3 says “Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.”
The first sentence is absolutely correct. But the second one means that RABS and isolators should be used for both processes of sterile products manufacturing: aseptic and with terminal sterilisation.
Their use should be considered in the CCS
But these two are fundamentally different. Terminal sterilisation means that the product is subject to sterilisation in the final sealed container. This assures sterility level is no worse than 10-6 reliably. No RABS or isolators are necessary or beneficial.
This idea is confirmed in another item in the subpart “Aseptic preparation and processing”: “8.9 Where possible, the use of equipment such as RABS, isolators or other systems should be considered in order to reduce the need for critical interventions into grade A and to minimize the risk of contamination….”
This is true and correct. RABS and isolators are restricted to aseptic processes only. As a suggestion: add the word aseptic process in item 4.3. To say: Restricted Access Barrier Systems (RABS) or isolators are beneficial for aseptic processes in assuring required conditions and minimizing microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators for aseptic processes should be justified.
Conclusion
Annex 1-2022 has some useful innovations, e.g. for personal. But it has absolutely unacceptable items for premises, classification and monitoring. Some of them repeat old dogmas, others make these dogmas even worse. Some items are senseless or turn the matter on its head and are in conflict with science and practice.
It means that Annex 1-2022 is unsatisfactory and shall be reviewed, e.g.:
- Limits for particles ≥ 5.0 μm shall be withdrawn both for start-up (classification) and monitoring, at last.
- A mandatory requirement for doors interlocking shall be eliminated and the solution on doors interlocking shall be left to the manufacturer’s competence as it was earlier.
- Slogans like “scientific approach” shall be avoided.
We do not discuss in this paper such “innovations” like CCS – Contamination Control Strategy. They bring nothing useful and new, except an image of “science” that distracts attention from real care on quality.