Manufacture of medicinal gases (Annex 6)

On this page: Manufacture of active substance gases | Training | Separation of medicinal gases from non-medicinal gases | Storage of empty and filled cylinders | Delivery of bulk gas into hospital tanks | Control of residual impurities | Batch numbering of cylinders | Transportation of packaged gases

Manufacture of active substance gases

Manufacturers are exempt from the PIC/S Guide to GMP requirements relating to bulk, liquified gas manufacture (Annex 6 clauses 1-3).

Training

All persons involved in the manufacture of medicinal gases should receive training relevant to their specific tasks and records of training should be maintained (Annex 6 clause 5).

All persons performing release for supply should be suitably trained and experienced in the manufacturing and test requirements of medicinal gases as well as the process of release for supply.

Separation of medicinal gases from non-medicinal gases

Manufacturers are required to implement controls to avoid mix-ups of products, which include separation of medicinal and non-medicinal gas production processes.

A ‘separate area’ for filling activities is usually achieved by filling medicinal gases on dedicated manifolds. Such an area should have sufficient space around to perform all the filling related tasks.

Storage of empty and filled cylinders

Gas cylinders should ideally be stored:

• under cover
• protected from the elements
• protected from potential contamination

Where justified by the manufacturer, it may be acceptable to store cylinders outdoors where the manufacturer implements controls including but not limited to:

• empty cylinders are checked to determine:
  • the cylinder has a positive pressure to ensure that it is not emptied
  • any faulty cylinders are quarantined and sent for further inspection and repair
• full cylinders have appropriate plugs and/or dust covers in place to protect the valve outlets

Prepare empty cylinders for filling under cover.

For filled cylinders, the level of cleanliness required in the storage area should be compatible with the expected environment in which they may be used by the customer.

Delivery of bulk gas into hospital tanks

Bulk liquified gas

Bulk liquified gas intended to be delivered into hospital tanks is exempt from:

• the operation of Part 3-3 of the Therapeutic Goods Act 1989 (Schedule 7 Item 17)
• Annex 6 clause 18 concerning records maintained for bulk gas intended to be delivered into hospital tanks, therefore does not apply to bulk liquified gas supplied in this manner

Bulk supply of non-liquified gases

Annex 6 clause 18 may apply to the bulk supply of non-liquified gases as the manufacture and supply of these gases is not exempt from the requirements of Good Manufacturing Practice.

Control of residual impurities

The stated maximum theoretical impurity level of 500 ppm v/v for a filling pressure of 200 bar at 15 °C (and equivalent for other filling pressures) (Annex 6 clause 32) will be understood to have been achieved by the required pre-fill cylinder preparation. Evidence that it is being achieved will be based on validation data, so routine testing will not be required.

Batch numbering of cylinders

Annex 6 requires that a batch be defined for filling operations (Annex 6 clause 31). Manufacturers should consider as a batch each group of cylinders filled:

• via a multi-cylinder manifold
• in an uninterrupted filling cycle, in case of cylinders filled one at a time

Numbering

The batch number:

• should be on each gas cylinder
• may be displayed on a separate label (Annex 6 clause 37)
• may be a validated unique identifier, such as an individual cylinder barcode label

Identification

Batch identification needs to:

• ensure traceability of a specific batch through all stages of manufacture and distribution (including all maintenance history)
• relate to each cylinder filled as part of the production batch manufacturing process

Traceability

To ensure adequate traceability of cylinders involved in a batch the following criteria concerning batch identification must be met:

• each filled cylinder must be traceable to significant aspects of the relevant filling operations
• the manufacturers cylinder control system must be able to identify all cylinders involved in a specific batch
• cylinders should be uniquely identifiable in human readable form to allow customers to identify and isolate cylinders involved in a specific batch in the event of recall action or a quality related incident
• The manufacturers’ cylinder control system must retain historic data for all batches a cylinder has been included in

Transportation of packaged gases

Filled gas cylinders should be protected during transportation (Annex 6 clause 45).

While Australian therapeutic goods regulations do not encompass good distribution practice (GDP) it is expected that the finished product will be released in a format that will provide adequate protection during transportation.

Where transportation of the packaged gases is likely to occur in open vehicles it is expected that cylinders will be fitted with appropriate plugs and/or dust covers to protect the valves, and such activities are recorded in the batch records.