Medicinal gases and good manufacturing practice (GMP)

Version 1.0, 25 May 2012

Good Manufacturing Practice (GMP) describes a set of principles and procedures that when followed helps ensure that therapeutic goods are of high quality.

The PIC/S guide to good manufacturing practice for medicinal products applies to medicinal gases. Interpretations of the PIC/S guide to GMP for medicinal gas manufacturers have been agreed by the TGA and the Australia New Zealand Industrial Gas Association.

Guide to interpretation of the PIC/S Guide to Good Manufacturing Practice for Medicinal Products – 15 January 2009; applicable to the manufacture of medicinal gases

About this guidance document

  • The following interpretations of the PIC/S Guide to GMP (15 January 2009) have been agreed between the TGA and the Australia New Zealand Industrial Gas Association. The tables will be updated as the need arises.
  • Any questions about these interpretations, or requests for interpretation of any other clauses, should be emailed to gmp@tga.gov.au

Version history

Version Description of change Author Effective date
V1.0 New document. Replaces previous interpretation table on the TGA website for the Australian Code of GMP for Medicinal Products (16 August 2002). Office of Manufacturing Quality 25/05/2012

Preamble

Medicinal gases are classified as medicines under the Therapeutic Goods Act 1989. The Manufacturing Principles 2009 determine that for the manufacture of medicines, compliance with the PIC/S Guide to Good Manufacturing Practice (GMP) - 15 January 2009 PE009-8 is required.

Schedule 7, entry 17 of the Therapeutic Goods Regulations 1990 exempts bulk liquefied medical gases from the operation of Part 3-3 of the Therapeutic Goods Act 1989.

Medicinal gas manufacturers have requested the TGA for additional guidance on the interpretation of the PIC/S Guide to GMP specifically for medicinal gas manufacture. After adoption at the time of the Australian Code of GMP (2002), which was based on the 2002 PIC/S Guide to GMP, the TGA has published a table on its web site summarising the interpretation of the Australian Code of GMP (2002) for medicinal gas manufacture.

Following the adoption of the 2009 PIC/S Guide to GMP, this guidance document has been developed in liaison with Australian medicinal gas manufacturers to replace that web site table.

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Interpretations of the basic GMP requirements (Chapters 1-9)

Note: all clauses not mentioned in the table are fully applicable.

Clause Interpretation
1.4(i) to 1.4(xii)

Product Quality Review (PQR)

New GMP section - relevant to medicinal gas manufacturers.

PQRs are not required for bulk liquefied gases.

PQRs are required for all compressed medicinal gases that are filled on-site.

"Medical air" needs to be included as part of the PQR if manufactured on-site by a batch wise production process (as per other compressed medicinal gases). Medical air is only subject to Part 1 of GMP and not subject to Part 2, due to the nature of its manufacture.

The requirement for conducting reviews of the stability monitoring programme will be exempt provided expiry dates are not put on the cylinder labels.

1.5 and 1.6

Quality risk management

New GMP section - relevant to gas manufacturers.

The new requirement for performing Risk Assessments is applicable to all TGA licensed manufacturers in Australia.

Annex 20 is voluntary. It provides useful guidance in the tools available for conducting Risk Assessments.

2.14-2.15 Not Applicable.
2.18 Not Applicable.
2.20 Not Applicable.
3.2 Replaced by specific requirements in Annex 6: clause 3.1.2
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 3.1.2 and 3.1.3).
3.9-3.14 Not applicable.
3.22 Not applicable.
3.26 Analysis for batch specific testing and for full cylinder analysis against the 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.
3.34 Not applicable.
4.14-4.15 On-site Medical Air production will be included in the TGA GMP inspection and that the control and quality of any bulk pharmaceutical product (BPP) manufactured on-site will be included in the scope of the TGA GMP inspection, but limited to the areas of quality control, transference, validation (including change control) and acceptance of the BPP prior to filling.
4.17 Batch processing records are applicable to all medicinal gases filled on site with specific details included in Annex 6, clauses 4.1 and 5.3.6.
4.18 The information to be entered in Batch Packaging Records is not applicable and is replaced by clause 4.1, Annex 6.
4.26 Environmental monitoring and pest control are not applicable.
4.29 Not required as equipment and areas are product specific.
5.8 Not applicable.
5.11 Not applicable.
5.12 Applicable to medicinal gas filling only.
5.18 Not applicable. Cross-contamination is prevented by specific requirements in Annex 6.
5.19 Not applicable. Cross-contamination is prevented by specific requirements in Annex 6, with the exception of clause 5.19(f) which is applicable to gas manufacturers.
5.29

Starting materials in the storage area should be appropriately labelled (see chapter 5, item 13). Labels should bear at least the following information:

  • The designated name of the product and the internal code reference where applicable; - Applicable
  • A batch number given at receipt; - Not applicable
  • Where appropriate, the status of the contents (e.g. quarantine, on test, released. Rejected); - Not applicable
  • Where appropriate, an expiry date or a date beyond which retesting is necessary. - Applicable

For medicinal gas manufacture, the term 'starting material' also refers to the empty gas cylinder.

5.32-5.34 Not applicable.
5.35-5.36 Applicable to mixed gas manufacturers only.
5.38-5.39 Applicable to mixed gas manufacturers only.
5.46 Not applicable.
5.54 Replaced by on-line checks in Annex 6.
5.56 Applicable to printed batch code labels only.
5.57 Applicable to printed batch code labels only.
5.62-5.64 Not applicable.
6.8 Under Section 20 of the Therapeutic Goods Regulations, licensed manufacturers must retain records at the licensed premises for at least 12 months after the expiry date of the goods or, if there is no expiry date, for not less than 6 years after completion of manufacture.
6.14 Not applicable.
6.15 No analytical method validation is required provided current EP/BP/USP monographs are adhered to.
6.23-6.33 Not relevant to medicinal gas manufacturers unless expiry dates are specified on the gas cylinder label.
8.7 New requirement relevant to gas manufacture:- Special attention should be given to establishing whether a complaint was caused because of counterfeiting.
8.8 New requirement relevant to gas manufacture - The Competent Authorities should be informed if a manufacturer is considering action following possible faulty manufacture, product deterioration, detection of counterfeiting or any other serious quality problems with a product.
8.16 Relevant to gas manufacture - The effectiveness of the arrangements for recalls should be evaluated regularly.

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Interpretations of Annex 6

Clause Interpretation
2.1 This does not prevent a trained independent operator who meets the criteria from being authorised to perform release for supply of medicinal gases.
3.1.1 A "separate area" is usually achieved by filling medicinal gases on manifolds dedicated to medicinal gases. Such an area should have sufficient space around to perform all the filling related tasks.
5.1 Chapter 5: clauses 5.21-5.24 and annex 6: clause 5.1 are interrelated and therefore annex 6 clause 5.1 is applicable to medicinal gas manufacturers. Validation is also discussed in Annex 11 and 15.
5.2.1-5.2.11

Clause 5.2.1: Bulk Gases produced outside the TGA licensed site and transported to the Gas manufacturer by tanker remain exempt from clause 5.2.1

Clause 5.2.2:- Applicable

Clauses 5.2.3-5.2.10: On-site Medical Air production will be included in the TGA GMP inspection and that the control and quality of any bulk pharmaceutical product (BPP) manufactured on-site will be included in the scope of the TGA GMP inspection, but limited to the areas of quality control, transference, validation (including change control) and acceptance of the BPP prior to filling

Clause 5.2.11:- This clause is relevant to all Gas manufacturers who receive bulk tanker deliveries

5.3.6
  • The first two dot points are applicable to cylinders fitted with pressure retention valves only
  • The minimum residual pressure will depend on the design specification of the residual pressure retention valve. For some valves this may be less than 3 to 5 bar

A recorded check to determine that the cylinder has a positive pressure which is demonstrated to be sufficient to ensure that the cylinder is not emptied will be required.

5.3.7 The stated maximum impurity level of 500ppm v/v will be understood to have been achieved by the required pre-fill cylinder preparation. Evidence that it is being achieved will not be required.
7.2

Gas cylinders have traditionally not been stored under cover and as this is not known to have caused any adverse effects, it continues to be acceptable provided that:

  • Empty cylinders are checked to determine that the cylinder has a positive pressure to ensure that it is not emptied and any faulty cylinders are quarantined and sent to the test workshop for inspection
  • Full cylinders have appropriate plugs and/or dust covers to protect the valve outlets
  • All activities are recorded in the batch specific log sheets
7.4

Gas cylinders have traditionally been transported in open vehicles. This is acceptable provided that:

  • Full cylinders have appropriate plugs and/or dust covers to protect the valves

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