Health Candana- Manufacture of sterile drugs

These guidelines interpret the requirements for manufacturing sterile products in Part C, Division 2, section C.02.029 of the Food and Drug Regulations (the Regulations).

Health Canada is an active participating member of the Pharmaceutical Inspection Cooperation Scheme (PIC/S). Health Canada has adopted the PIC/S guidance Annex 1 Manufacture of Sterile Medicinal Products which describes how to manufacture sterile drugs in compliance with C.02.029 of the regulations.

Guidance documents like this one are meant to help industry and health care professionals understand how to comply with regulations. They also provide guidance to Health Canada staff so that the regulations are enforced in a fair, consistent and effective way across Canada.

Health Canada inspects establishments to assess their compliance with the Food and Drugs Act (the Act) and associated regulations. When we conduct an inspection, we will use this document as a guide in assessing your compliance with GMP requirements for sterile products.

These guidelines are not the only way GMP regulations can be interpreted, and are not intended to cover every possible case. Other ways of complying with GMP regulations will be considered with proper scientific justification. Also, as new technologies emerge, different approaches may be called for.

Guidance documents are administrative and do not have the force of law. Because of this, they allow for flexibility in approach. So use this guide to help you develop specific approaches that meet your unique needs.

General

The manufacture of sterile products should be carried out in clean areas, the entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.

The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories: firstly those where the product is terminally sterilised; and secondly those which are conducted aseptically at some or all stages.

Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.

In order to meet “in operation” conditions, these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.

The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms.

For the manufacture of sterile drugs, 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. Unidirectional 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 uni-directional flow 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.