1. EU GMP Annex 1 and ISO 14644
Prepared by Tim Sandle

2. Agenda What is likely to go into the revised Annex 1, including:
Terminal sterilisation vs aseptic processing
WFI produced by reverse osmosis
Guidance for media simulation trials
This remains speculative
Changes to cleanroom classification (ISO 14644)
This is factual, based on the newly published standard
Prepared by Tim Sandle

3. Part 1 – What to expect from eu gmp annex 1
May 2016
© 2016

4. Information sources
Comments submitted on the position paper dated March 2015.
Comments submitted by ISPE, France A3P, CEN TC243, UK PHSS.
Presentations by Andrew Hopkins – MHRA and lead for the EMA/PICs joint revision process.
PHSS Annual meeting London September 2015.
ISPE Europe Annual Meeting Frankfurt March 2016.
Pharmig Irish Conference 2016.
Tim Sandle ISO presentation for Pharmig.
Caution – This presentation is based on Pharmig’s assessment of information released so far – the final version might be different.
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5. Process
Early 2017 – a new version of EU GMP Annex 1 – for sterile products manufacture – is expected.
May 2016
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6. Annex 1 – Last revision Revision completed December 2007.
Into operation 1st March 2009
Major changes were:
Alignment with EN ISO :1999 (for 5 micron particles)
Media simulation update
Changes to bioburden testing (in relation to pre-final filtration – set at 10 CFU/100mL)
Capping of vials.
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7. Minor revision 2010
Minor update in 1st March 2010 for the vial capping changes.
This was a requirement for Grade A air supply
This version was transferred into PIC/S; but, required a Q&A paper to clarify various matters (e.g. “Grade A air supply”).
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8. Annex 1 – The current revision process
In 2012, the German (ZLG) presented a concept statement on revision the the EMA IWG.
Work started February 2015.
Joint EMA & PIC/S process (first time).
Initial joint “concept paper” issued by EMA & PIC/S dated 20th March (EMA/INS/GMP/735037/2014).
There was little substance about the revision in the “concept paper”.
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9. Annex 1 – Nature of the issues/subjects identified so far…
Typographical errors.
Update to accommodate revisions to ISO & 2: 2015.
Update to accommodate the PIC/S Annex 1 Q&A clarification document.
Deal with lack of clarity in some clauses.
Fill gaps in information.
Update to recognize the maturing of some technologies & practices since 2007.
Some new areas – WFI & biofilms.
Deal with industry & regulatory concerns.
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10. What do we know about the contents and structure so far?
Refresh the requirement of all GMPs
Will only consider sterile products (no application of Annex 1 to non-sterile products).
The existing structure and sections will be retained.
It will be a revision, NOT a re-write.
Will be better organised:
Have cleanliness classes and levels more clearly defined. Will better explain “Grade A air supply”.
Everything to do with environmental monitoring will be together; and improve the definition of the approach for lower grade areas (B, C & D).
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11. Environmental monitoring
Will all be in one place.
Emphasises it is an essential part of QRM.
Viable
Non-viable
Media process simulations
Large scale & campaign or “tail-gate” simulations.
Small scale.
Essential to understand the risks process/product/facility
Description of the requirement for trending
First time trending will be mentioned
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12. Limits No change to limits proposed.
BUT averaging at a location over time will no longer be OK.
When the limit for a micro level is <1, then we need to look at frequency of occurrence – a nod towards USP <1116>
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13. Aseptic Processing Focus on keeping operators away from the product.
Update approach to newer technologies Isolators & RABS (restricted access barrier systems).
RABS likely to be described as ‘open’ and ‘closed’
Address closed process systems:
Sterilise in place.
Integrity proving.
Media fills
No longer to specify number of vials – each facility must risk assess an appropriate number
Small batch size issues, some guidance likely on appropriate media process simulations.
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14. Isolators & RABS
Today, we would see Isolators and RABS as essential technology that should at least be considered.
Perhaps the revised Annex 1 should say?
“The utilisation of barrier technologies, RABS and Isolators can improve the sterility assurance during open aseptic processing, and should be considered when selecting the environmental control solution.”
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15. Maturing technology aseptic connectors
The evolution of closed systems, including disposables/single-use, requires some improved guidance because the risks are different:
CIP & SIP (clean-in-place; sterilise-in-place)
Integrity of aseptic connection devices.
Integrity of closed systems.
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16. Water Biofilms: Guidance on WFI:
Increasingly seen as high profile by regulators.
Need to risk assess biofilms in water systems
Guidance on WFI:
New EP WFI Monograph allowing membrane technologies to be used.
Means WFI can be produced by distillation or reverse osmosis
MHRA have expressed concerns with this due to endotoxin risk.
Interesting to see what Annex 1 says about this.
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17. Typographical errors in current Annex 1
So, what does this mean?
0.45 +/- 20%, or a range?
Where is the working position?
Mix of ‘UDAF’ and ‘LAF’ throughout
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18. Confusion examples Is this clear to you?
51. Changing rooms should be designed as airlocks and used to provide physical separation of the different stages of changing and so minimize microbial and particulate contamination of protective clothing. They should be flushed effectively with filtered air. The final stage of the changing room should , in the at-rest state, be the same grade as the air into which it leads. The use of separate changing rooms for entering and leaving clean areas is sometimes desirable. In general hand washing facilities should be provided only in the first stage of the changing rooms.
Is this clear to you?
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19. Part 2 –changes to iso 14644 parts 1 and 2
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20. ISO 14644
New version went live in December 2015, for two parts of the standard:
ISO Classification of air cleanliness
ISO Specifications for testing and monitoring to prove continued compliance (i.e. routine / on-going monitoring)
Both parts deal with particles only
Companies have until 31st December 2016 to implement the changes.
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21. ISO Part 1 - purpose
Classification is the process of qualifying the cleanroom environment by the number of particles using a standard method.
Determine classification of cleanroom according to standards e.g. Room x is ISO class y.
Distinct from routine environmental monitoring.
Distinct from process monitoring e.g. ongoing assessment of aseptic filling.
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22. Changes #1: Particles
Allows for one or more particle sizes to be assessed.
The standard requires the larger particle to be at least 1.5 times that of the smallest particle size measured.
But no longer features ≥5.0 µm limit for particles for the Grade A equivalent class for classification.
This does not replace EU GMP requirements. ≥0.5 and ≥5.0 µm need to be assessed for monitoring.
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23. Changes #2: Number of locations
New approach to selection of locations for particle counting
Reminder - previous approach:
NL = A
NL is the minimum number of sampling locations (rounded up to a whole number).
A is the area of the cleanroom or clean zone in square metres (m2) for which the square root is taken.
Taking the surface of the room in square metres, assessing the square root and using the obtained number (rounded up) to give the number of locations, to be positioned equidistantly.
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24. Changes #2: Number of locations
The change:
No calculations are required to determine the number of locations - there is a ‘look-up table’ (Table 1 - the only reference for all sizes of particle from ISO 1 to ISO 9).
This method has generally led to an increase in particle count locations.
Each location is treated independently and there is 95% level of confidence that at least 90% of the cleanroom will comply with the maximum particle limit for the intended class.
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25. Changes #2: Number of locations
An example of what the changes mean:
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26. Changes #3: Position of particle counters in a cleanroom
Once the number of locations has been selected, the room is divided up into equal sectors and a particle counter placed in each sector.
Previous standard – counter placed in approximate centre.
New standard - where the counter is placed within each sector is determined by the user.
The standard allows counters always to be placed at the same point within the sector; randomly placed within the sector; or evenly distributed; or by risk.
Reason: counts no longer assumed to be homogenous within a sector.
Addition locations can be added at the discretion of the facility.
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27. Changes #3: Position of particle counters in a cleanroom
To align with GMP, the location should be orientated to the point of greatest risk e.g. close to fixed equipment. The standard recommends that the following is accounted for:
Room layout;
Equipment layout;
Airflow patterns;
Position of air supply and return vents;
Air-change rates;
Consideration should be given to any unintended bias in the sampling process.
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28. Changes #4: Particle counter sampling volumes
Volume of air to be sampled at each location, the volume of air must be sufficient to detect at least 20 particles for the largest particle size limit.
The operative figure is ≥5.0 microns
Volume to be sampled (Vs) =
[20 x 1000 (constant)]
Class limit particles (largest size)
For example, Grade C
Volume to be sampled
= 20 x 1000 = 0.69 litres
29,000
Therefore, a minimum of 1 litre would need to be taken at each location.
However, ISO states that the volume needs to be at least 2 litres, sampled over a one minute period.
Therefore, a minimum of 2 litres would need to be taken at each location.
Prepared by Tim Sandle

29. Changes #4: Particle counter sampling volumes
For example, EU GMP Grade B cleanroom:
Volume to be sampled =
20 x 1000 = 6.9 litres
2,900
Therefore, a minimum of 7 litres would need to be taken at each location.
Note: Grade A is more complicated (explained later)
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30. Changes #4: Particle counter sampling volumes
For example, consider a Grade B cleanroom:
How long would this take to monitor? See over...
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31. Changes #4: Particle counter sampling volumes
Continuing with our cleanroom example.
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32. Changes #5: No more intermediate classes
What does this mean for EU GMP Grade A cleanrooms?
The Grade A issue
EU GMP Grade A does not equal ISO class 5, because of the different 5.0 µm limits
29 count limits for ISO class 5
20 count limit for EU GMP Grade A.
Where intermediate classes are required the standard no longer permits increments of 0.1. So, to meet EU GMP, an ISO class of 4.5 would need to be selected in theory.
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33. Changes #5: No more intermediate classes
Options:
Just classify Grade A for 0.5 µm and use 0.5 µm / 5.0 µm for operations,
Or continue with 20 or 29 as a limit as an additional option for 5.0 µm.
Standard states: “In some situations, typically those related to specific process requirements, alternative levels of air cleanliness may be specified on the basis of particle populations that are not within the size range applicable to classification.”
This means continuing with one cubic metre per location.
BUT attempting this for 5.0 µm size particle could be difficult due to potential particle loss from tubing.
Most people are attempting to classify for both particle count sizes but much will depend on what the EU GMP Annex 1 revision says.
Prepared by Tim Sandle

34. Summary So the revisions mean:
In general, the number of particle counter locations increase in a cleanroom.
However, the sample volumes decrease
Except for Grade A where because of the 5.0 micron issue, 1 cubic metre is still needed at each location
Locations are no longer place equidistantly but selected by risk assessment.
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35. Changes #6: Averaging is no longer allowed
With previous standard it was possible to fail a location in a cleanroom but to pass the cleanroom overall if the particle counts averaged at a value below the class limit.
There is no longer a ‘grand total’ for the cleanroom, each individual sector must pass.
A cleanroom is determined to have met the ISO class provided that the obtained result at each location does not exceed the desired class.
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36. Changes #6 Example of some results:
Grade B cleanroom, assessed for 0.5 µm particles using a 1-minute counter
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37. Changes #7: Probe location & tubing
The particle counter probe must be orientated into the airflow (for unidirectional air) or pointed upwards for turbulent flow air.
There are no changes to occupancy states, the ideal position is that cleanrooms should be classified when occupied (at the normal occupancy level).
Particle counter tubing length is reduced for a maximum of 3 metres to a maximum of 1 metre.
To avoid ‘drop out’ of particles
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38. Changes #8: Test certification
Certification for classify a cleanroom must contain:
Name and address of the testing organization.
Date of testing.
No. and year of the publication of the relevant part of ISO e.g. ISO 14644: 1 – 2015.
Location of cleanroom (or clean zone).
Specific representation of locations e.g. diagram.
Designation of cleanroom:
ISO class (plus EU GMP)
Occupancy.
Particle count sizes considered.
Test method used (and any departures or deviations).
Identification of test instrument and calibration certificate.
Test results.
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39. Changes #9: Particle counters
Recommendation that particle counts that meet ISO are used (error rate at each particle size of no more than ±20%). Counters must be certified.
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40. Thank you Any questions?
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