If you do business in Europe and are installing a clean room that deals with the manufacture of Sterile Medicinal Products, your clean room must adhere to the most recent set of standards set forth in the “Revision of the Annex to the EU Guide to Good Manufacturing Practice-Manufacture of Sterile Medicinal Products.”

Clean room classifications can be confusing. It is important to understand the clean room classifications to:

a) understand what standard to adhere to when commissioning your design, and

b) how to do it in a cost-effective manner.

General Considerations

The standards require that the manufacture of sterile products be done in clean areas with entry into the areas through airlocks, whether by personnel or equipment and materials. Air passing into the area should do so through filters with designated efficiency. Various operations, including component preparation, product preparation, and filling, are required to be done in separate areas within the clean room.

Manufacturing operations are divided into two categories: those where the product is terminally sterilized, and those that are aseptically conducted at some or all stages.

Further, these clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment to minimize the risks of particulate or microbial contamination of the product or materials being handled.

Meeting in-operation conditions in clean room areas requires that each area reach specified air-cleanliness levels in at-rest occupancy rates. At-rest is the state where the installation is complete and all equipment is installed and operating but without the presence of operations personnel.

Grade Definitions for the Manufacture of Sterile Medicinal Products

Normally, there are four grades or levels of manufacturing required when manufacturing sterile medicinal products.

Grade A – this defines the local zone for high-risk operations like filling zone, stopper bowls, open ampoules and vials and, making aseptic connections. In normal situations, these conditions are provided by a laminar air flow workstation. A laminar flow system provides a homogeneous air speed of 0.45 m/s +/- 20% at the working position.

Grade B – this provides the background environment for grade A zone items needing aseptic preparation and filling.

Grade C and D – areas graded C and D are used for performing less critical tasks that are carried out during less critical stages in the manufacturing process.

Wondering about Federal Standard 209E and ISO approximate equivalents?

Grade A is equivalent to class 100 or ISO 5

Grade B is also equivalent to class 100 or ISO 5

Grade C is equivalent to class 10,000 or ISO 7

Grade D is equivalent to class 100,000 or ISO 8

Maintaining these environments

Cleanroom Grades A – D should employ a broad range of techniques and cleaning practices to meet these guidelines. This includes an air circulation system that works effectively. The use of HEPA filters and ULPA filters aid in air circulation and removal of particulate from the environment.

Additional measures should be taken by cleanroom personnel to further minimize risk for contamination.

This includes:

Cleanroom sticky mats upon entry

Ensure the proper cleanroom garments are worn. See cleanroom gowning requirements for more information.

Clean surfaces using appropriate cleanroom wipes and sterile wipes when necessary

Clean larger surfaces using tacky rollers and or cleanroom mops

Cleanroom Limits for Airborne Particulate Contamination

Clean room and clean air device classification, in relation to GMP (2008).
Cleanroom Standard		Maximum permitted number of particles /m³
EU GMP Grade	ISO 14644-1	At rest ≥0.5µm	At rest ≥5.0µm	In operation ≥0.5µm	In operation ≥5.0µm
A	5	3,520	20	3,520	20
B	5	3,520	29	352,000	2,900
C	7	352,000	2,900	3,520,000	29,000
D	8	3,520,000	29,000	Not defined	Not defined