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Management & Implementation of the Revision to Annex 1 – relationship with ISO 14644-1:1999
Gordon FarquharsonBovis Lend Lease Technology
November 2008
My role in ISO & CEN
• A Chartered Engineer• UK expert to ISO TC 209 WG 1, 3, 4 & 7.• Convenor of ISO TC 209 WG1. • Chairman of CEN TC 243 ~ ISO Standards into
the CEN community. =EU + EFTAWorked with EMeA in 2006/7 to help resolve airborne particle classification issues in Annex 1 of the EU GMP.
• Chairman of UK’s BSI LBI/30 Committee which is responsible for Cleanroom & Contamination Control standards in the UK.
• Technical responsibility in the CONSULTING & PROJECT DELIVERY activities of Bovis Lend Lease Technology Division.
Agenda
• Status of Annex 1 EU GMP• Comments about PIC/S GMP• The revised airborne particle
requirements• Impact on classification of
Pharma/Life Science cleanroom and clean air devices
• Impact on real-time monitoring systems
Remember !Remember !Not just an EU market problem. Same requirement in Not just an EU market problem. Same requirement in PIC/S GMP and similar in WHO GMPPIC/S GMP and similar in WHO GMP
Let’s look at the key changes to Annex 1 of
the EU GMPNote: The scope of changes is based on EMeA interested parties
meeting December 2006 & CEN 243 input to EMeA, and the actual revision of Annex 1 published by the EC in February 2008.
• Summary of the changes: • The basic scope and requirements has not changed. • The differentiation between cleanroom classification and
monitoring has been improved significantly.• There is a clear requirement to classify “at rest”, classify “in
operation” and monitor “in operation”.• There is a clearer requirement for automated particle monitoring
systems for Grade A & Grade B areas.• The ⟨5.0 micron particle limit for Grade A & B have been modified
to reflect the practicality and sensitivity of particle counting.• The sample size requirements for classification and monitoring
will be clearer.• There are NEW requirements for the clean environment for
capping Vials.• New media fill requirements are aligned with FDA.• Some formatting improved to help clarity.
Feb 2008 Changes to Annex 1
EU GMP - Particles & MicroMay 03 OLD/CURRENT version
At Rest In Operation
Grade Max Particles ⟨ stated sizes Microbiological
0.5µ 5.0µ 0.5µ 5.0µ Air
sample cfu/m3
90mm settle plate
cfu/4hr
A 3 500 1 3 500 1 <1 <1
B 3 500 1 350 000 2 000 10 5
C 350 000 2 000 3 500 000 20 000 100 50
D 3 500 000 20 000 Not
defined Not
defined 200 100
How 2003 Annex 1 deals with 1 particle limit
• In 14644-1, 1 particle limit requires 20m3 sample.• 2003 Annex 1 recognised this and allows us to do
this:
• This actually prevents formal classification to ISO 14644-1:1999
EU GMP – Annex 1 Particles & MicroThe Feb 2008 version
At Rest In Operation
Grade Max Particles ⟨ stated sizes Microbiological
0.5µ 5.0µ 0.5µ 5.0µ Air
sample cfu/m3
90mm settle plate
cfu/4hr
A 3 520 20 3 520 20 <1 <1
B 3 520 29 352 000 2 900 10 5
C 352 000 2 900 3 520 000 29 000 100 50
D 3 520 000 29 000 Not defined
Not defined 200 100
The magic 20 particles
• Comes from ISO 14644-1:1999• For classification, the air sample size
shall be sufficient such that if you were at the class limit for the largest considered particle size, you would count at least 20 particles.
• Rule of thumb to give some confidence that real particles are > noise in the system.
The False Count Risk 1 part/ m3 (limit)
It’s all about the probability of finding 1 particle/m3, and that
there is also the possibility the the count is a FALSE COUNT. Of course it might also be a
real one.
False counts (noise)
EU GMP count limit
How ISO 14644-1:1999 Deals with False Counts
ISO states that you have always have sufficient sample that if you were at the class
limit, you would get a count of at least 20 particles.
This is stated to make sure that REAL COUNTS are like
to beat FALSE COUNTS.
False counts (noise) 1m3 sample
Class count limit
EU GMP Basis for Classification
• If we use ISO 14644-1:1999 and the Annex 1 table we get the following minimum sample volumes at each location (sampling rate 28.3 litre/min• Grade A 20 part/m3 ≥5.0µà 1 000 litre• Grade B (at rest) 29 part/m3 ≥ 5.0µà 690 litre• Grade B (operational) 2 900 part/m3 ≥ 5.0µà 28.3 litre• Grade C (at rest) 2 900 part/m3 ≥ 5.0µà 28.3 litre• Grade C (operational) 29 000 part/m3 ≥ 5.0µà 28.3 litre• Grade D (at rest) 29 000 part/m3 ≥ 5.0µà 28.3 litre
“In operation” Classification
• Now a clear requirement.• Need to develop a risk based justification for
periodic or for cause “in operation” classification.• Questionable of wise to do this during media
process simulation.
Classification example 10x5m UDAF EU GMP Grade A + ISO 14644-1:1999
Annex 1-2003 Annex 1-2008Each Location Sample Size1000/8=125 litres 1000 litres
10 x 5 m
8 sample locations (min)
X X X X
X X X X
• Sample locations - 50 m2
# sample locations 8• Sample size each location
Grade A (at rest & operational)0.5µ= 3 500 5.0µ= 1Sample size 1000/8=125 litresSample NOT 14644-1 compliant
• Sample timeSample rate 28.3 litre/minTime/Sample 5 minsTotal sample time 40 mins
• Sample locations - 50 m2
# sample locations 8• Sample size each location
Grade A (at rest & operational)0.5µ= 3 520 5.0µ= 20Sample size 1000 litres
• Sample timeSample rate 28.3 litre/minTime/Sample 36 minsTotal sample time 288 mins
Classification example 10x5m UDAF EU GMP Grade A + ISO 14644-1:1999
Annex 1-2003 Annex 1-2008
• Sample locations - 50 m2
# sample locations 8• Sample size each location
ISO 5 class limit0.5µ= 3 500 5.0µ= 1Sample size 1000 total /8=125 litresThis Sample NOT 14644-1 compliant
• Sample timeSample rate 28.3 litre/minTime/Sample 5 minsTotal sample time 40 mins
• Sample locations - 50 m2
# sample locations 8• Sample size each location
Grade A (at rest & operational)0.5µ= 3 520 5.0µ= 20Sample size 1000 litres
• Sample timeSample rate 100 litre/minTime/Sample 10 minsTotal sample time 80 mins
Classification example 10x5m UDAF EU GMP Grade A + ISO 14644-1:1999
Annex 1-2003 Annex 1-2008
“In operation” Monitoring – Grade A
• The practical issues of airborne particle monitoring during set-up yet to be challenged.
• Still retains the option of monitoring a simulated operation if the product is inherently hazardous to the particle counting system.
“In operation” Monitoring – Grade A
• Suggests the principle of a practical basis for developing a monitoring system.
• Recognises that the process can generate aerosols.Not only restricted to ≥5.0 micron, will affect ≥ 0.5 also!
“In operation” Monitoring – Grade B
• Suggests a similar principle of a practical basis for developing a monitoring system.
• Recognises that RABS are present a lesser risk than poorer separative devices.
“In operation” Monitoring – Systems
• Sets out basic requirements.• Recovery of 5.0 micron particles will
dictate the nature and capability of the system.
• Recognises some of the contamination risks that can affect particle monitoring systems.
• Revision of ISO 14644-2 and UK PHSS monograph will address the configuration & use of such systems.
“In operation” Monitoring – Systems
• Recognises that sample size and frequency of sampling need to be developed on a risk basis.
• Need also to refer back to clause 9 as this is more helpful.
“In operation” Monitoring – Systems
• This is contentious.• FDA guidance doesn’t recognise this occurrence.• Research by Whyte & Eaton and Lujunqvist & Reinmuller
suggests that ≥ 0.5 micron and ≥ 5.0 micron rise together. Remember the ≥ 0.5 includes all the ≥ 5.0s.
“In operation” Monitoring – Systems
• Gives us more flexibility for Grades C & D.• Be careful not to develop over onerous compliance rather
than risk based monitoring.• “Clean-up” time means recovery test.• Doesn’t automatically demand recovery testing of all
Grade C & D areas !
MANIFOLD PARTICLE MONITORING SYSTEM
Computer
Manifold
Data collection points (DCP)
Data collection points
Manifold control
Pump
Counter
MANIFOLD TUBING PARTICLE DROPOUT
Particle loss in manifold sample tubing, 15mm diameter,1000l/min flow rate(courtesy Particle Measuring Systems)
Example Monitoring Alert & Action Levels
• Typical settings for monitoring software are as follows:
• ≥0.5 micron – Alert 2000/m3 normalised in each 28.3 litre sample.
• ≥0.5 micron –Action 3500/m3 normalised in each 28.3 litre sample
• ≥5.0 micron – Alert 12/m3 cumulative 1000 litre sample + <3 per 28.3 litre sample + if 3 28.3 litre samples or more out of 5 have a count of 1 or more à trigger alert.
• ≥5.0 micron – Action 20/m3 cumulative 1000 litre sample or >3 per 28.3 litre sample or if >3 28.3 litre samples or more out of 5 have a count of 1 or more à trigger action.
Where do we go from here?
• Now have a GMP that fits better with ISO.• The whole basis for considering >=5.0 micron particles is
poor founded. Cost time and money to comply.• 5.0 micron requirement NOT harmonised with
US/Japanese practice.• WHO even worse (ZERO limit @ ≥5.0 micron).
• Need science based information.• Establish a research project:
• Academic Institution• Industry sponsored – 20 international pharma firms.• 2-3 year programme• Academic research. Data Evaluation. Experimentation.
Vial capping
• A clear requirement quoting 2 basic options.• (1) Aseptic process.• (2) Clean process with local clean air protection.
• There isn’t any defined requirement about the environment surround local protection for option (2)
• Grade A air supply is quite different from designating a Grade A zone.
This presentation has been preparedand delivered by:-
Gordon J FarquharsonBovis Lend Lease, Technology
Consultants and EngineersTanshire House, Shackleford Road,
Elstead, Surrey, GU8 6LB, UKtel +44 (0)1252 703 663fax +44 (0)1252 703 684cell +44 (0)7785 265 909
e-mail [email protected]