EU GMP Annex1 Review

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

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

PART 1 – WHAT TO EXPECT FROM
EU GMP ANNEX 1
May 2016 © 2016 3

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 14644 presentation for Pharmig.
Caution – This presentation is based on Pharmig’s assessment of
information released so far – the final version might be different.

Process
• Early 2017 – a
new version of
EU GMP Annex 1
– for sterile
products
manufacture – is
expected.
May 2016 Prepared by Tim Sandle 5

Annex 1 – Last revision
• Revision completed December 2007.
• Into operation 1st March 2009
• Major changes were:
– Alignment with EN ISO 14644-1:1999 (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.

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”).
http://www.picscheme.org/publicati
on.php?id=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 2015
(EMA/INS/GMP/735037/2014).
• There was little substance about the revision in the
“concept paper”.

Annex 1 – Nature of the issues/subjects
identified so far…
• Typographical errors.
• Update to accommodate revisions to ISO 14644-1 & 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.

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).

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

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>

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.

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.”

Isolators
• A view of the U.K. MHRA,
likely to be included in
Annex 1, not to accept
VHP as a sterilisation
process and only as a
sanitising process.
• This means all product
contact parts which go
into an isolator must be
sterilised (autoclave or
irradiation) prior to VHP
processing.
May 2016 © 2016 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.

Water
• Biofilms:
– 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.

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

Confusion examples
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?

PART 2 –CHANGES TO ISO 14644
PARTS 1 AND 2

ISO 14644
• New version went live in December 2015, for
two parts of the standard:
– ISO 14644-1 - Classification of air cleanliness
– ISO 14644-2 - 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.

ISO 14644 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.

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.

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.

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.

An example of what the changes mean:

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.

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.

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 14644 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.

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)

volumes
For example, consider a Grade B cleanroom:
How long would this take to monitor? See over...

volumes
Continuing with our cleanroom example.

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 14644 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.

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.

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.

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.

Changes #6
• Example of some
results:
Grade B cleanroom,
assessed for 0.5 µm
particles using a 1-
minute counter

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

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 14644
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.

Changes #9: Particle counters
• Recommendation that
particle counts that
meet ISO 21501 are
used (error rate at each
particle size of no more
than ±20%). Counters
must be certified.

Thank you
Any questions?

EU GMP Annex1 Review

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