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Medicinal gases guidance
Version 2.0, January 2019
Production (Chapter 5)
The following guidance, on demonstrating compliance with the PIC/S guide to GMP has been formulated in relation to the following:
- in Australia, the production of bulk liquified gases is exempt from compliance with the PIC/S Guide to GMP
- the filling/manufacture of medical air starts with the compression of air and the medical air compressors, and all filling operations, should comply with Part 1 of the PIC/S Guide to GMP
Yields and reconciliation of quantities
We expect manufacturers of medicinal gas to:
- perform batch label reconciliation when cylinders have printed batch labels applied
- keep records of the quantity of batch labels printed, used and destroyed
We generally do not expect manufacturers of medicinal gas to perform:
- checks on yields
- reconciliation of quantities (clause 5.8)
Loss of medicinal gas occurs during manufacturing and can be variable, even under normal operating conditions.
To determine if the amount of medicinal gas, or gas mix, in a container is the amount and type indicated by the label, it is sufficient to:
- fill to a predetermined and acceptable temperature and pressure limit, or mass target
- perform finished product testing
Working with dry materials
Clause 5.11 does not apply to the manufacture of medicinal gas, as dry materials are not normally used.
Precautions against cross-contamination
Contamination control applies to the manufacture of medicinal gases.
Relevant sections of the PIC/S Guide to GMP include:
- Clauses 5.18 and 5.19: provide general principles
- Annex 6: provides specific guidance regarding the required controls
The manufacture of medicinal gases uses closed equipment. However, the re-use of cylinders without adequate precautions could lead to contamination by a wide variety of contaminants.
Periodic critical revalidation
Where a validated state has had no significant changes, a review with evidence that facilities, equipment and processes meet the prescribed requirements fulfils the need for periodic critical revalidation under clause 5.24.
The evidentiary review could be performed in conjunction with the PQR process.
Labelling of starting materials
Starting materials for medicinal gases include:
- empty gas cylinders (reused packaging material)
- cylinder product labels (not generally replaced each filling cycle)
- bulk gases (liquified or compressed gases stored in dedicated storage or buffer tanks)
Due to the unique product format of medicinal gases, not all requirements in clause 5.29 for labelling starting materials during storage apply.
Labelling requirements for starting material during storage that do apply to medicinal gases include:
- the designated name of the product and/or the internal code reference
- where appropriate, an expiry date or a date beyond which retesting is required
- for medicinal gas manufacture, the term 'starting material' also refers to the empty gas cylinder
Labelling requirements for starting material during storage that do not apply to medicinal gases include:
- a batch number given at receipt
- where appropriate, the status of the contents (e.g. quarantine, on test, released, rejected)
Dispensing of starting materials
Dispensing activities (clauses 5.32-5.34):
- are not applicable to the manufacture of medicinal gases
Medicinal gas manufacture does not encompass dispensing of starting materials for later use in batch production. Bulk product is filled directly into the cylinders using closed equipment.
Intermediate and bulk products
The requirements for area clearance (clause 5.35), and intermediate and bulk storage (clause 5.36) are applicable to the manufacture of mixed medicinal gases only.
Products and batch details to be displayed
For the purposes of demonstrating compliance with clause 5.46 there is no requirement to display the name and batch number of the product being handled at the packaging line when the following are met:
- medicinal gas is filled on dedicated filling equipment and the equipment is labelled accordingly
- filling equipment is appropriately identified/labelled with the gas type
Controls should be in place to verify electronic code readers are operating correctly, such as cylinder bar code scanners (clause 5.52).
Control of product during packaging
The basic principles outlined in clause 5.54 for on-line control of product during packaging are insufficient to adequately control the production of medicinal gases. Detailed requirements for production of medicinal gases are outlined in the relevant 'Production' section of Annex 6 clauses 19- 38.
Reconciliation of batch labels
Reconciliation of quantities for medicinal gas manufacture is limited to printed batch labels only.
Investigate discrepancies before release of the product (clause 5.56).
Destroy unused printed batch labels, and record the destruction (clause 5.57).
Due to the nature of medicinal gas manufacture, the reworking of gases is not expected.
The requirements of clauses 5.62-5.64:
- do not apply where reprocessing or rework are not performed
- do apply only in situations where reprocessing or rework of gases (specifically re-labelling) occurs