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

Time to comply

• 12 & 24 months to comply.• Capping note confusing (all vials)

Basis for Classification & Monitoring

• Table a clear basis for classification & monitoring.

OR, how the “5.0 micron particle limit problem” has been eased !!!!!!

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

So where does the magic 20 particles come from?

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

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

• A clear basis for developing the monitoring system.

“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)

Filling Machine Particle Monitoring

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.

CleanProtected

Aseptic

Questions???

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 gordon.farquharson@eu.bovislendlease.com