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.
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.
The airborne particulate classification for these grades is given in the following table:
|maximum permitted number of particles/m^3 equal to or above|
|Grade||at rest (b)||in operation||Federal Standard 209E and the ISO classifications approximate equivalency|
|0,5m m||5m m||0,5m m||0,5m|
|A||3 500||0||3 500||0||100, M 3.5, ISO 5|
|B(a)||3 500||0||350 000||2 000||100, M 3.5, ISO 5|
|C(a)||350 000||2 000||3 500 000||20000||class 10000, M 5.5, ISO 7|
|D(a)||3 500 000||20 000||not defined (c)||not defined (c)||class 100000, M 6.5, ISO 8|
(a) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grades A, B and C.
(b) The guidance given for the maximum permitted number of particles in the “at rest” condition corresponds approximately to the US Federal Standard 209E and the ISO classifications as follows: grades A and B correspond with class 100, M 3.5, ISO 5; grade C with class 10000, M 5.5, ISO 7 and grade D with class 100000, M 6.5, ISO 8.
(c) The requirement and limit for this area will depend on the nature of the operations carried out.
Specific airborne particulate classifications for these grades are specified in the appropriate documentation.
Related: ISO 14644 Cleanroom Standards