PIC/S GMP Guide
For the manufacture of sterile medicinal products
The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.
For the manufacture of sterile medicinal products 4 grades can be distinguished:
|Grade A||The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.|
|Grade B||For aseptic preparation and filling, this is the background environment for the grade A zone.|
|Grade C and D||Clean areas for carrying out less critical stages in the manufacture of sterile products|
Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in the following table:
For classification purposes in Grade A zones, a minimum sample volume of 1m³ should be taken per sample location.
For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles ≥5.0 μm.
For Grade B (at rest) the airborne particle classification is ISO 5 for both considered particle sizes.
For Grade C (at rest & in operation) the airborne particle classification is ISO 7 and ISO 8 respectively.
For Grade D (at rest) the airborne particle classification is ISO 8.
For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.
|Maximum permitted number of particles/m³
equal to or greater than the tabulated size
|At rest||In operation|
|D||3,500,000||20,000||not defined||not defined|
Examples of operations to be carried out in the various grades are given in the table below :
|Grade||Examples of operations for terminally sterilised products|
|A||Filling of products, when unusually at risk|
|B||Preparation of solutions, when unusually at risk. Filling of products|
|D||Preparation of solutions and components for subsequent filling|
|Grade||Examples of operations for aseptic preparations|
|A||Aseptic preparation and filling|
|B||Preparation of solutions to be filtered|
|D||Handling of components after washing|