It is critically important that Users and Service Providers align on technical requirements for utilities prior to design, installation, and qualification. Otherwise, a user may not get a system that fulfills their needs (User Requirements Specification).
The International Organization for Standardization’s (ISO) standards are developed to ensure a common language/framework for users and service providers to agree on, and accept responsibilities for, the final quality of the system that is being requested/provided. So, if we simply categorize a need as ISO 8, which I will explain in a minute, the applicable standards vary, so facilities experts in the pharma industry need to be very specific about their requirements or they may end up with equipment (or a cleanroom) they cannot use.
First, a bit of background. In the aseptic manufacturing spaces of the biopharmaceutical industry, ISO 8 is commonly meant to define the maximum non-viable particulate permitted per ISO 14644 (Cleanroom and Associated Controlled Environments standards), plus viable organism limits set by national regulatory authorities through FDA Guidance Documents [1] or European Union (EU) [2] rules. In addition to the specific allowable limits, there also must be demonstrated control through appropriate engineering design of filtration, room air changes, differential pressures, etc.
ISO 8573 is the group of standards relating to the quality of compressed air. Interestingly, within this group of standards, ISO 8 also has a defined meaning. There are 10 listed purity classes which each define the maximum permissible amount of contamination allowed in a cubic meter of compressed air. Contaminants are defined as solid particulate, water, and oil, and each ISO purity class (0 – 9) permits an increasingly greater amount of contamination.
And now to the question that motivated me to write this article. As a user, if I specified that the compressed air entering my classified cleanroom was required to meet ISO 8 requirements, what standards/specifications would an engineer use to design a system that would fulfill my user requirement?
If the engineer was from a cleanroom design company, they would likely design the compressed air system to deliver air with the same quality as the specifications of the environment into which the air is introduced in compliance with ISO 14644-1:2015, i.e., not more than 3,520,000 particles ≥ 0.5µm per cubic meter, and based upon US / EU regulations not more than 100 CFU/m3 for an active air sample, and not more than 50 CFU/m3 for passive air sample (settle plates). NOTE: CFU is Colony Forming Unit. They would also design the compressed air system to have particulate filtration, an extremely low amount of oil, and a moisture content that would preclude condensation from forming inside the delivery system.
If the engineer was from a company that built and sold compressed air and associated purifying equipment (dryers / coalescing filters / particulate filters), then the quality of the air would no doubt meet ISO 8573-1:2010, ISO 8 requirements, which are seen to be significantly different from 14644:2015 requirements. Particulate is allowed to be between 5 and ≤10 mg/m3, which indicates significantly more than 3,520,000 individual particles (≥ 0.5µm), moisture is allowed to be between 0.5 and ≤5 g/m3 (which could allow microbial growth), and oil content is allowed to be >5 mg/m3! Clearly, air of this quality is not acceptable for use in pharmaceutical manufacturing.
When misunderstandings or misinterpretations of a specification occur, the results can be catastrophic. ISO 8 is not always the ISO 8 you thought it was, so make sure you are very, very precise in the questions you ask as you choose a vendor.
[1] Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, September 2004
[2] Eudralex The Rules Governing Medicinal Products in the European Union, Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, August 2022
Bob Ferer, QxP Vice President, is a 30+-year veteran in pharma. Prior to joining QxP in 2012, Bob worked as an independent consultant. His roles have typically been facility and utility design/build projects, equipment procurement, qualification/validation, and facility start up. An engineering chemist by training, Bob supports QxP project teams from a compliance and regulatory aspect for the design, testing, qualification, and validation for facilities, critical utilities, maintenance, equipment, engineering, and manufacturing processes. Bob’s experience and insights have been very valuable to QxP clients.
Check out Bob’s two blogs about mistakes not to make when retrofitting facilities: Don’t Be a Daredevil When Retrofitting Your Facility, Part 1, and Don’t Be a Daredevil When Retrofitting Your Facility, Part 2.
