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Cleanroom Classifications (using ISO 14644-1)

Written by: Domhnall Mc Gowan M.Sc.

Classification of laboratory and cleanroom spaces can be divided in to two main categories. Category 1 is classified based on air cleanliness, and category 2 is based on biosafety or containment requirements. The distinguishing feature on what type of classification you should be considering is based on the activity that will be carried out in the space. In this article we will be talking about classification of cleanrooms based on air cleanliness, or quantification of airborne particles.

Cleanrooms are primarily classified by the quality of the air, which means that the air quality must meet certain criteria for particle quantity and size per cubic meter (m3) or cubic foot (ft3) of air sampled. Cleanrooms are used to manufacture sensitive medical and electronic products. Small particles can severly impact the quality of these products. Electronics such as semiconductors can malfunction if introduction of small particles occurs during production, and terminally sterilized or aseptically produced medical products such as drugs and stem cell therapies can illicit severe reactions if particles adulterate them.

Defining Classifications

There are many governing or regulatory bodies which lay out requirements for production of sensitive products depending on the product type and geographical location of the manufacturing facility.

ISO-14644

When it comes to classification of airborne particles the International Organization for Standardization publishes guidelines which are adopted and incorporated by all the major global regulatory bodies. Specifically for cleanroom classification based off quantification of airborne particulates they publish ISO-14644-1: Classification of air cleanliness by particle concentration. This guideline lays out the cleanroom classification categories and the specifications for each category in terms of particle size and quantity. Those categories are:

 

Maximum allowable concentrations (particles/m3) of particles equal to and greater than the considered size

ISO Class0.1µm0.2µm0.3µm0.5µm1.0µm5.0µm
ISO110-----
ISO21002410---
ISO31 00023710235--
ISO410 0002 3701 02035283-
ISO5100 00023 70010 2003 520832-
ISO61 000 000237 000102 00035 2008 320293
ISO7---352 00083 2002930
ISO8---3 520 000832 00029 300
ISO9---35 200 0008 320 000293 000

Table 1: ISO-4644-1 cleanroom classifications

US Food and Drug Administration (FDA

The US FDA, and associated federal bodies, publish the Code of Federal Regulations (CFR). 21 CFR Part 211 specifies the requirements for producing drug products and alongside the Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing document they lay out the cleanroom classification requirements that need to be met when manufacturing drug products. In their guidance they make some modifications:

i) Focus on ISO designations 5-8.
ii) Assign equivalent Clean Area Classifications (particles/ft3)
iii) Focus on 0.5µm particle sizes
iv) Include microbiological air specifications

See Table 2 and 3 for further information.

European Union (EU)

The EU and its related governing bodies publish their own directives which lay out the requirements for classification of cleanrooms. Similar to the FDA they incorporate and expand on ISO-14644-1. EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products outlines the classification requirements for cleanrooms producing medicinal products. In this guidance they categorize areas as follows:

i) Areas are classified as Grade A, B, C, or D
ii) Specify particle requirements for 0.5 µm and 5.0 µm particle sizes
iii) Provide specification for “at rest” and “in operation” states.
iv) Provide microbiological limits for specified grades

See Table 2 and 3 for further information.

Other Governing Bodies

The FDA and EU are two of the main governing bodies however many countries will have their own, and there are also other international bodies which provide regulatory guidelines on the classification of cleanrooms. These other bodies generally follow the lead of either the FDA or EU, or just wholly incorporate ISO-14644-1.

 Maximum allowable concentrations of particlesFDA (particles/ ft3)EU
(particles/ m3)
Class0.5µm (ft3)0.5 µm (m3)5.0 µm (m3)ClassAt restIn operation
ISO51003 520-100Grade A
Grade B
Grade A
ISO61 00035 2002931 000
ISO710 000352 000293010 000Grade CGrade B
ISO8100 0003 520 00029 300100 000Grade DGrade C

Table 2: Comparison of ISO -14644-1, FDA cGMP and EU GMP specifications for cleanroom classifications based on particle quantification criteria. Modified from ISO-14644-1, EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products, and FDA Guidance for Industry: Sterile Drug Product Produced by Aseptic Processing.

ISO ClassFDAEU GMPGrade
Air sample (cfu/m3)Settle plate (cfu/4hours)Air sample (cfu/m3)Settle plate (cfu/4hours)Contact plate (cfu/plate)
ISO511No growthNo growthNo growthA
ISO673
ISO71051055B
ISO8100501005025C
ISO920010050D

Table 3: Comparison of microbiological limits set by FDA cGMP and EU GMP for equivalent clean spaces. Modified from EudraLex Volume 4 Annex 1: Manufacture of Sterile Medicinal Products and FDA Guidance for Industry: Sterile Drug Product Produced by Aseptic Processing.

Validation and Maintenance of Cleanrooms Classifications

To truly state that a cleanroom meets the above classifications it must be validated against the specifications set out by the regulatory body. This is an initial process of data gathering over a set period of time and then an ongoing process where air quality is routinely monitored for particles. Specialized equipment and technical documentation are needed to carry out this validation process. Additionally, time must be spent maintaining the systems and components which ensure the air quality continues to meet the specifications.

How Vibraclean can help

Vibraclean are experts in facility monitoring and maintenance. We can be your partners in developing your cleanroom validation and maintenance plan. Vibraclean also act as sterility maintenance providers and can provide guidance on SOP development and training of your facility personnel.

2022-05-11T15:54:36-04:00
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