Controlled Environments - July/August 2017

One of the biggest challenges in any cleanroom is setting up a suitable monitoring program. Which instruments are used, how frequent samples should be, how much sampling is required, what guidelines need to be followed? All of these questions need a firm understanding of the different technologies capturing cleanroom air samples in portable particle counters and air samplers, as well as a firm grasp on cGMP and regulatory guidelines.

Let’s start by reviewing the current guidelines; then let’s look at the technologies used to capture air samples and the evaluation of these samples to verify your cleanroom is compliant to the classification it was designed to operate in.

In terms of cleanroom classification, ISO 14644- 1:2015 classification of air cleanliness by particle concentration is the current guideline that has been widely used internationally. The update in 2015 was significant in terms of particle counter sampling volumes in ISO 5 environments, as well as a new lookup table based on cleanroom area and the number of sampling locations. There are nine ISO classes based on the level of air cleanliness—ISO 1 being the highest.

In pharmaceutical aseptic manufacture, ISO 14644-1 is the main standard used to classify or certify cleanrooms worldwide as a unified international standard. In 1989 the European Union adopted its own GMP guide to Good Manufacturing Practice, which was equivalent to PICs GMP guide, which was updated on Jan. 1, 2017. The original PICs Basic Standards came out in 1972, derived from the WHO GMP Guide. The aim of these standards and the continuous improvements to the documentation ensure high-quality medicines are produced.

Therefore, following the
latest guidelines and under-
standing how to implement
them is an important factor when developing an
environmental monitoring program and classifying
or routinely testing the classification status of your
cleanroom in at rest or operational conditions.

ISO 14644-1 and cGMP comparisons

• ISO 14644-1:2015 table has 9 ISO Classes

• ISO 14644-1:2015 table focuses on ≥0.1μm, ≥0.2μm, ≥0.3μm, ≥0.5μm, ≥1.0μm and ≥ 5.0μm particle sizes

• In ISO 14644-1:2015 ≥ 5.0μm size is makes classification inappropriate based on low concentrations and potential particle losses in the sampling system

• PICs PE 009-13 GMP Guide has 4 Classes, Grade A-D

• PICs focuses on 0.5 and 5.0μm particle sizes

• Each table is based on a sample of 1 cubic meter

• PICs PE 009-13 GMP Guide has an “At Rest” and “In Operation” Cleanroom state

• For Grade A the particle concentrations are identical

• For Classification in Grade A zones a minimum of 1m³ sample volume is required

• Grade A is considered IS0 4. 8 when ≥ 5.0μm are considered

• Grade B (at rest) is considered to be equivalent to ISO 5 for ≥0.5μm and ≥ 5.0μm

• Grade C (at rest and in operation) is equivalent to ISO 7 and ISO 8 respectively

• Grade D (at rest) equivalent to ISO 8.

• PICs PE 009-13 GMP Guide states that the ISO 14644-1 methodology to define the number of sampling locations and the sample size based on the class limit of the largest considered particle size is to be followed.

How are cleanrooms classified?

Using an Airborne Particle Counter

For classification based on non-viable particles an airborne particle counter is used to classify a cleanroom and either ISO or PICs tables are used. An airborne particle counter cannot distinguish between a viable and non-viable particle, so all particle types are counted. Non-viable particles are known to act as vehicles for viable particle transportation in