Contamination Control

EU GMP Annex 1:2008 and Particle Counting: Part 2

Welcome to the second in a series of three application notes to assist end users in understanding guidance detailed in EU GMP Annex 1 it follows on from directly from Part 1. In Part 1, introductory paragraphs up to and including section 3 were covered. In Part 2, sections 4 to 7 detailing cleanroom and clean air device classification will be covered.

Cleanroom and Clean Air Device Classification

Section 4:

Cleanrooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table. Maximum permitted number of particles per m3 equal to or greater than the tabulated size At rest In operation Grade A B C D 0.5 m 3 520 3 520 352 000 3 520 000 5.0 m 20 29 2 900 29 000 0.5 m 3 520 352 000 3 520 000 Not defined 5.0 m 20 2 900 29 000 Not defined

EU GMP Annex 1 makes a clear distinction here regarding cleanliness classification and process monitoring activities. Sections 4 to 7 describe cleanroom and clean air device classification, sections 8 to 15 describe cleanroom particle monitoring. An organization should not be using ISO 14644-1 to determine the number of particle monitoring locations. Particle monitoring is covered in more detail later. Classification is being discussed here. EU GMP Annex 1: 2009 references EN ISO 14644-1 to describe how to classify a clean zone for particulate cleanliness, which includes: How many locations to sample with a particle counter within a graded zone How much sample volume to take at each sampling location within a graded zone How to process and present the collected data from the graded zone

EU GMP Annex 1 does provide a target classification table (above) for each of the graded areas for at rest and in operation conditions. It is important to understand a few points relating to this table. EU authorities are interested in 0.5 m and 5 m particles (Note: FDA cGMP requires 0.5 m only). The particulate cleanliness levels detailed in this table agree exactly with whole number ISO classifications as found in ISO 14644-1 (ISO 5, ISO 7, etc.), except for Grade A @ 5.0 m, see section 5 for more detail. This table has been modified several times during the last 7 years, specifically the 5.0 m limit. This has increased from 0 #/m to 1 #/m and then to the value seen today - 20 #/m. The current value of 20 #/m fits the ISO 14644-1 statistical model, this requires that a volume of air be sampled such that 20 particles be counted at the target classification limit for the largest considered particle size. No Grade D in operation limits are specified in the table, however an organization should define in operation limits, and these should be based on historical data and risk analysis.

Section 5:

For classification purposes in Grade A zones, a minimum sample volume of 1 mshould be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles 5.0 m. For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected. It is extremely important to understand the impact of the requirement to count 0.5 m AND 5.0 m particles when classifying a clean zone, particularly for a Grade A zone. The limit of 20 #/ m @ 5.0 m means that large sample volumes must be taken by a portable particle counter when classifying a clean zone. Inserting the value of 20 into the single sample volume formula as detailed in clause B.4.2.1 of ISO 14644-1:1999, the result is a single sample volume of 1 m. A 1 cfm portable particle counter takes over 35 minutes to sample this volume, a 50 lpm particle counter takes 17 minutes and a 100 lpm unit takes 10 minutes. It is this requirement to classify at 5.0 m that is driving the need for high flow rate portable particle counters. For Grade A zones for in operation and at rest conditions, EU GMP Annex 1:2008 recognizes that 20 #/m @5.0 m does not yield a whole ISO classification number (ISO 14644-1 does allow for classifications that are not whole numbers). EU GMP Annex 1 states that Grade A classification is ISO 4.8 in operation and at rest, this is dictated by the largest considered particle size, which is 5.0 m.

The use of portable particle counters

Section 6

Portable particle counters with a short length of sample tubing should be used for classification purposes because of the relatively higher rate of precipitation of particles 5.0m in remote sampling systems with long lengths of tubing. Isokinetic sample heads shall be used in unidirectional airflow systems. It is well understood by EU inspection authorities that long lengths of particle transport tubing have an adverse impact on large particle recovery, particularly at 5.0 m. It is preferable therefore to keep the sample tubing as short as possible when classifying a clean zone. Ideally a direct mount isokinetic probe should be used where practicable (see picture below). Regulators will expect to see Isokinetic Probes used either as a direct mount probes or on the end of the particle transport tubing, when sampling in an Page 2 of 3

environment when there is uni-directional (laminar) airflow and non uni-directional (turbulent) airflow. Note the new terms for laminar and turbulent airflow.

Portable counter with direct mount isokinetic sample probe

Section 7

In operation classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation is required for this. EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications. EU GMP Annex 1 is describing cleanroom re-qualification in this section. ISO 14644-2 details proposed re-qualification frequencies for demonstrating continued cleanroom compliance. There is a level of expectation that the Grade A zones should be re-qualified every 6 months, Grade B every 6 months at rest and annually in operation, Grade C and D zones annually. If an organization decides on an alternative approach, then this should be justified, the basis for such a justification could be on historical monitoring particle count data.
To be continued

Part 3, third and final application note in this series, will cover relevant sections from section 8 onwards of EU GMP Annex 1. These sections contain detail on particle monitoring.

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