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Medicinal gases guidance

Version 2.0, January 2019

15 January 2019

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Premises and equipment (Chapter 3)

Due to the method of manufacture of medicinal gas, not all of the requirements of Chapter 3 of the PIC/S Guide to GMP are applicable.

Outlined below are the sections of Chapter 3 of the PIC/S guide to GMP that are either:

  • not applicable
  • superseded by information in Annex 6
Clause Interpretation
3.2 Replaced by specific requirements in Annex 6: clause 8
3.3

Lighting should be adequate for the tasks being performed by the filling operators.

Temperature is only relevant when calculating the settled pressure of the gas.

Ventilation of the gas filling area must be adequate for safety reasons in the event of gas leakage.

Humidity is not relevant to closed filling systems.

3.4 Not applicable
3.6 Not applicable
3.7 Applicable (replaced by specific requirements in Annex 6: clause 8)
3.9-3.14 Not applicable
3.22 Not applicable
3.26 Batch specific testing and full cylinder analysis against product specifications (i.e. BP/EP/USP monographs), should be performed using equipment that is appropriately calibrated, maintained and where applicable utilise validated systems.
3.29 Not applicable
3.31 Not applicable
3.33 Not applicable
3.43 Not applicable

Environmental controls for filling operations

Manufacturers are responsible for ensuring that the environmental conditions during manufacture are suitable (clause 3.3). TGA's basic expectations for environmental controls are that:

  • lighting should be adequate for the tasks being performed by the filling operators
  • temperature controls are only relevant when calculating the settled pressure of the gas
  • ventilation of the gas filling area must be adequate for safety reasons in the event of gas leakage
  • humidity control is not relevant to closed filling systems

Pest control

The requirements relating to pest control (clause 3.4) are not relevant to medicinal gas manufacture.

Precautions against cross-contamination

The prevention of cross-contamination events should be assured by the use of robust engineering controls for filling equipment. The principle of clause 3.6 applies to the manufacture of medicinal gases in that adequate precautions should be taken to prevent cross-contamination.

Annex 6 contains information about the required controls.

Design and control of production areas

Production areas for the manufacture of medicinal gas:

  • do not require clean-rooms, filtered air environments or similar controls (clauses 3.9 – 3.14)
  • do not normally involve the preparation or exposure of starting materials or primary packaging materials

Cylinder storage and sampling

Medicinal gas manufacture:

  • has basic requirements relating to storage capacity (clause 3.18) and design (clause 3.19)
  • has no requirement for a separate sampling area for staring materials (clause 3.22)

Annex 6 contains information about cylinder storage.

Printed packaging material storage

Cylinder product labels can be:

  • changed at several points in the manufacturing process
  • made available at multiple areas of the facility such as:
    • test shop
    • filling ramps
    • maintenance area

For the purposes of clause 3.25, the minimum requirements to demonstrate 'safe and secure storage' of cylinder product labels are to:

  • keep bulk quantities of cylinder product labels secure in a restricted storage area to exclude unauthorised access
  • provide secure separate locations for quarantined and released cylinder product labels (clause 3.21)
  • keep only a minimal number of approved cylinder product labels in the production areas, e.g. enough for one week's production
  • store cut labels in separate, closed containers to avoid mix-ups (clause 5.41)
  • provide secure, lockable storage of released-to-production cylinder product labels at the end of shifts in all areas of the facility

Quality Control laboratories

Quality Control laboratories should generally be separated from production (clause 3.26); however, where testing activities do not pose a risk to product quality they may be conducted within the production environment.

Perform batch specific testing against the product specification using equipment that is appropriately calibrated, maintained, and where applicable, utilise validated systems.

Detailed requirements for quality control of medicinal gases are outlined in the relevant 'Quality Control' section of Annex 6 clauses 39-44.

Ancillary areas

Medicinal gas manufacturers:

  • are required to provide toilets appropriately located for the number of users
  • not required to provide facilities for changing clothes and hand washing (not GMP critical requirements, clause 3.31)

Cleaning and sanitisation

The PIC/S Guide to GMP (PE009-13) contains limited detail on requirements for cleaning and sanitisation specifically related to medicinal gas manufacturers.

Closed pressurised systems and equipment used for medicinal gas manufacture, only needs cleaning between batches if exposed to a contaminant.

Manufacturers should retain appropriate records when cleaning pressurised systems and equipment prior to use in commercial production, for example after:

  • post qualification and commissioning
  • any closed system breaches to the system's integrity

(Annex 6 clause 15, Annex 15 clause 3.1).

Process water

Distilled or deionised water is not normally used in the production of medicinal gases.

The hydrostatic testing of cylinders can use town (drinking) water (Annex 6 clause 26):

  • Use a risk-based approach when considering the need to sanitise water pipes within the hydrostatic test station, particularly for processes that recirculate water through multiple testing events
  • Document:
    • written procedures describing microbiological testing of process water used in the hydrostatic testing of cylinders
    • action limits for microbiological contamination, and measure

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