Sterile Manufacturing Premises

This article will look into sterile manufacturing premises as outlined in EU GMP annex 1

Sterile Products according to EU annex 1, sterile product refers to one or more of the sterilized elements exposed to aseptic conditions and ultimately making up the sterile active substance or finished sterile product. These elements include the containers, closures, and components of the finished drug product. Or, a product that is rendered sterile by a terminal sterilization process.

Manufacturing of sterile products should take place in cleanrooms. Cleanrooms are controlled environments which are meant to reduce contamination. These cleanrooms are closely monitored for contamination such that people, equipment and materials should pass through an airlock. These cleanrooms must also meet set standards of cleanliness in terms of accepted particle and microbial concentration

?EU GMP annex 1 outlines 4 types of cleanrooms which are listed below

Grade A

It is also referred to as the critical zone

High risk procedures/processes which require lowest levels of contamination are carried out in this area.

The zone contains physical barrier systems that encloses operations from environment to minimize contamination, these systems include Restricted Access Barrier System (RABS) or Isolators

Grade A utilizes unidirectional airflow (UDAF) and airflow velocity systems. Airflow velocity system ensures that the airflow is controlled such that airborne contaminants are cleared effectively

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Grade B

This zone surrounds Grade A cleanrooms. Aseptic preparation and filling take place in this cleanroom. RABS system can be found in these cleanrooms

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Grade C and D.

In these rooms, less critical procedures take place here

Isolators can also be placed in these cleanrooms

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Design of the premises should allow observations into cleanroom A and B from outside by using transparent material (such as glass) or make use of cameras to allow for supervision of work without the need for entry

?The following tables summarizes particle and microbial contamination levels permitted per each Cleanroom grade

Airlocks

According to EU GMP, airlock is an enclosed space with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude ingress of particle matter and microorganism contamination from a lesser controlled area

From the definition, the main aims of the airlock system are to prevent microorganism contamination and maintain cleanliness levels. It does so by acting as a barrier and only entry/exit between cleanrooms of different grades. Illustration of an airlock is shown below

From the diagram, ideally there should be unidirectional flow of air preferably from higher grade cleanroom to a less grade cleanroom. High grade cleanroom should have higher air pressure than the airlock and the airlock should have a higher air pressure than the less grade cleanroom. This is to prevent contaminants from moving from lesser cleanroom grade to a higher cleanroom grade.

The recommended pressure difference between cleanrooms should be at least 10 Pa as shown in diagram above. A warning system should be in place to alert personnel on any decrease in pressure differences and a procedure should be in place to address the warning alert. At planned intervals, airlocks should be flushed with filtered air to remove any contaminants and maintain cleanroom grade

Airlocks for personnel and material movement should be separated. In the case where it’s not possible, time-based movement separation of personnel/material should be considered and done in a planned procedural manner.

When not in operation “at rest”, the cleanliness grade of airlock should be the same as the higher cleanroom grade which it leads into.

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Personnel Airlocks

Are meant to be used by personnel entering a high-grade cleanroom. Interlocking door system is mainly preferred which doesn’t allow opening of entry and exit doors simultaneously.

Personnel should adhere to change room procedures which include gowning procedures. Separated airlock for entry and exit into grade B cleanroom is preferred. If not feasible or CCS does not indicate risk of contamination, time-based separated movement of entry and exit should be done in planned procedural manner

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Material Airlock

It is an airlock used for transferring materials and equipment between cleanrooms.

Materials to enter must be approved. If materials are moving from low grade cleanroom to high grade cleanroom, it must be clean and/or disinfected to prevent contamination