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Medicinal gases guidance

Version 2.0, January 2019

15 January 2019

Book pagination

Quality management (Chapter 1)

Quality management applies to the manufacture of all therapeutic goods to which the PIC/S guide to GMP (PE009-13) applies, including medicinal gases.

Terminology for quality management

The following quality management terms apply to manufacturing of medicinal gases:

Pharmaceutical Quality System

The latest PIC/S Guide to GMP, replaces the terminology 'Quality Management System' with 'Pharmaceutical Quality System' (PQS). This is in line with:

  • ICH Q10 global harmonisation efforts
  • PIC/S harmonisation efforts
  • aligning the GMP guide with contemporary principles of quality systems management

The new terminology better reflects the specific design elements and requirements for a quality system used to manage the manufacture of medicinal products.

The PQS approach described is applicable to the manufacture of all therapeutic goods to which the PE009-13 applies.

As medicinal gas manufacture is only a small component of most Australian gas manufacturing operations it is not necessary for manufacturer's documents to specifically refer to a Pharmaceutical Quality System.

Manufacturing authorisation

The term 'manufacturing authorisation', generally refers to the licence to manufacture therapeutic goods issued by the TGA to domestic manufacturers. For manufacturers located overseas, this would refer to the certificate of GMP compliance issued following an inspection.

Marketing authorisation

Marketing authorisation is the approval given to supply a therapeutic good in Australia, and, in most cases, involves entry on the Australian Register of Therapeutic Goods (ARTG).

The marketing authorisation includes the details of the product in the Australian Register of Therapeutic Goods (ARTG), as well as all other matters in relation to product registration, listing or inclusion agreed in writing between the TGA and the sponsor, and any other requirements imposed by a relevant Delegate of the Secretary upon ARTG entry.

Examples of regulatory requirements include, but are not limited to:

  • compliance with standards and registered formulations
  • special storage and transportation conditions
  • shelf life
  • packaging and labelling
  • batch release testing requirements
  • manufacturers are responsible for ensuring their PQSs are designed and operated to ensure all relevant requirements of the marketing authorisation are observed during the manufacture of therapeutic goods
  • holder of the marketing authorisation

The holder of the marketing authorisation is the product sponsor.

Change management

Regulated changes

Regulated changes include any manufacturing change that affects the registered product details.

Regulated changes:

  • are included as requirements for the marketing authorisation of therapeutic goods
  • require an application to vary the marketing authorisation

Please refer to Australian Regulatory Guidelines for Prescription Medicines (ARGPM).

These requirements are mandatory and are in addition to the requirements of the PIC/S Guide to GMP (PE009-13).

Change control applies to all GMP-related activities

Change control applies to all GMP-related activities undertaken by a manufacturer, not just to validation activities (clause 1.4 xii, xiii).

Change control and risk assessment requirements within the PIC/S Guide to GMP (PE009-13) apply to both:

  • regulated changes
  • other changes that have the potential to impact product quality

Verify all implemented changes for effectiveness through a change control process, including, but not limited to, changes to existing:

  • processes
  • systems
  • facilities
  • equipment
  • products
  • documents

The effort and extent of change control processes should be:

  • commensurate with the nature of the change
  • based on risk management principles

Verify that all changes implemented are effective following implementation.

Managing deviations

Manage deviations and other similar events according to the PIC/S Guide to GMP (clause 1.4 xiv). The guide clarifies the expectations for investigating deviations, including:

  • adequate root-cause-analysis
  • identification of corrective and preventative actions

Monitor and assess the effectiveness of such in line with quality risk management (QRM) principles.

Release for supply

Release for further processing (RFFP) and release for supply (RFS) are conducted by authorised persons. For more guidance see:

The manufacture of medicinal gases is the subject of Annex 6 of the PIC/S guide to GMP.

Unique features of medicinal gas manufacture

The manufacture of medicinal gas products differs from that of other medicinal products. These differences necessitate altered expectations for RFFP and RFS.

Features of medicinal gas manufacture:

  • use of re-useable packaging (gas cylinders)
  • bulk product manufacture in non-GMP licensed facilities
  • packaging testing in non-GMP licensed facilities
  • absence of stability programs
  • dispersed location of multiple manufacturing sites

There are often multiple manufacturing sites across the country for one medical gas product. It is not practical to have a centralised manufacturing site because logistical constraints make it desirable for the bulk production sites and cylinder-filling sites to be located as close as possible to the end users.

The number and dispersed location of manufacturing sites make it necessary for authorised persons to be allowed to conduct RFFP and RFS from locations that are remote from the actual manufacturing site.

Process flowchart for medicinal gas RFS

Medicinal gas:
1. bulk product manufacture at a non-GMP licensed facility (Site 1)
2. possible RFFP (AP1)
3. Receipt of bulk product at domestic site (Site 2)
4. possible RFFP (AP2)
Gas cylinders:
1. returned valved cylinders (Site 2)
2. periodic testing as required by AS2030.5 within Site 2 or at external site (no requirement for cylinder testing stations to hold a TGA licence) 
3. pre-fill inspection (Site 2)
4. Relabelling (Site 2)
Medicinal gas filling (Site 2), followed by one of the following:
1. release for supply (AP2 located at Site 2) or
2. release for supply (AP3 located at remote Site 3)

Bulk manufacture

The site of bulk manufacture, Site 1, will typically be one of the following:

  • a non-GMP licensed Australian facility
  • an overseas facility with or without TGA GMP clearance
GMP licence not required

Bulk manufacture of medicinal gases does not need to be in a GMP-licensed facility (item 17, Schedule 7 of the Therapeutic Goods Regulations 1990).

Analysis at Site 1

Site 1 performs analysis for identity and purity and the subsequent generation of a certificate of analysis of the bulk product.

Quality agreement between sites 1 and 2

When sites 1 and 2 operate under separate quality management systems, there should be a quality agreement between the two facilities to ensure that the manufacturer of the bulk product notifies the manufacturer at Site 2 of any:

  • significant deviations from the agreed production process for the bulk gas
  • out-of-specification results
  • non-compliance with quality management systems
  • investigations
  • complaints
  • other matters that may potentially affect product quality adversely
Transportation and RFFP

Transportation of bulk product to Site 2 can be before or after RFFP of the bulk product.

RFFP of bulk product

You should ensure that the quality of the delivered bulk gas is acceptable (clause 21 of Annex 6 of the PIC/S guide to GMP).

RFFP of the bulk product can be done:

  • by an authorised person (AP1) at the bulk manufacturing site, despite this site not being GMP-licensed
  • by an authorised person (AP2) at the GMP-licensed Site 2

This RFFP is limited to:

  • checking for the availability of a certificate of analysis
  • verifying:
    • the product's identity
    • the purity is within pre-defined specifications

We do not require the authorised person to do more than this because the bulk manufacturing facility is usually not GMP-licensed or GMP-cleared.

Quality of cylinders

Empty valved medicinal gas cylinders are:

  • returned to an Australian GMP-licenced medicinal gas filling facility
  • refilled and re-used repeatedly
Periodic testing of returned cylinders

Requirements for periodically inspecting and testing gas cylinders are specified in AS 2030.5 Gas cylinders – filling, inspection and testing of refillable cylinders.

These inspections and testing:

  • do not need to be in a GMP-licensed facility
  • can be at Site 2 or external to Site 2
  • are performed at a certified gas cylinder test station, which are required to
    • satisfy the requirements of PIC/S guide to GMP
    • be audited annually for re-certification purposes be an external qualified certifier
  • shall be in accordance with AS2337.1 and AS2337.3:
    • gas cylinder test stations - General requirements, inspection and tests - Gas cylinders
    • gas cylinder test stations - Transportable gas cylinders - Periodic inspection and testing of composite gas cylinders (ISO 11623:2002, MOD)
Third party gas cylinder test stations

If you engage third party gas cylinder test stations:

  • use a contractor qualification process

put in place a quality agreement that clearly defines GMP responsibilities and obligations of the contractor(clause 28 of Annex 6 of the PIC/S guide to GMP).

Microbial monitoring program

Water used in the hydrostatic pressure testing of gas cylinders must be at least of drinking water quality (clause 26 of Annex 6 of the PIC/S guide to GMP).

If you use an external contractor to monitor water quality, you need to have a quality agreement with the contractor to ensure immediate reporting to Site 2 of anomalous or out-of-specification results that might have the potential to impact product quality adversely.

Pre-fill inspection of cylinders

Prior to filling, inspect all returned cylinders for assessment of suitability for re-use in accordance with quality and functionality criteria specified in clause 30 of Annex 6 of the PIC/S guide to GMP.

Labelling

Label each container as described in clause 37 of Annex 6 of the PIC/S guide to GMP.

Filling and post-filling of cylinders

Use gas cylinders that have passed the quality inspection and fill with medicinal gas from the bulk product in accordance with the marketing authorisation.

There should be checks that each container is properly filled (clause 34 of Annex 6 of the PIC/S guide to GMP).

You may define a batch of liquefied medicinal gas product, by specifying a period of continuous filling.

Release for supply of medicinal gases

The RFS authorised person should have a thorough knowledge of the production and control of medicinal gases. So long as the person meets the criteria for being authorised to perform release for supply of medicinal gases, the authorised person can be a trained independent operator.

The authorised person must review appropriate documentation and release the product:

Using a remote authorised person for release for supply

If you use a remote authorised person (AP3):

  • Site 2 and Site 3 should operate under one quality management system

OR

  • there should be a GMP agreement between the two facilities defining responsibilities in regard to release for supply
Documentation for RFS

For RFS of medicinal gases, include documentation to demonstrate:

  • appropriate pre-fill inspections of cylinders have been conducted and all cylinders used in the batch are acceptable for use
  • the medicinal gas has been tested according to its specification
  • each cylinder in the batch is appropriately labelled with its batch number
  • appropriate checks have been conducted to ensure all containers have been filled
  • each cylinder within the batch has been tested for leaks and fitted with tamper evident seal
Verifying the quality of starting materials

For release for supply, the authorised person is required when possible to verify the original quality characteristics of starting materials. For medicinal gas products, it is not possible to do this for all starting materials because the quantity of bulk product, packaging and its accessories are not:

  • allocated to a specific finished product batch
  • reconciled for a batch (e.g. product labels, valves, dust caps etc.)

This is due to:

  • the characteristics of the bulk product (cryogenic liquid)
  • losses due to natural vaporisation
  • the re-use of packaging and most items associated with it
Ensuring traceability

You are expected to be able to trace:

  • gas cylinders
  • contents

You are not expected to be able to trace other components of medicinal gas products. This is because all accessories stay on the gas cylinders unless unfit for use (e.g. product labels, valves, dust caps, etc.), at which point they are replaced at the appropriate manufacturing step. The accessories are not allocated to a specific batch.

No ongoing stability program

Unless specified otherwise in the marketing authorisation, medicinal gases do not have a nominated shelf life, so you do not need an ongoing stability program.

Senior management responsibilities for GMP and quality management

Particular emphasis is placed on the roles and responsibilities of senior management who have ultimate control over manufacturing facilities and activities (new clauses, including clause 1.5).

Senior management hold the responsibility:

  • to ensure that the manufacturing activity is managed appropriately
  • to ensure adequate resources are available (human, financial and physical)
  • for the effectiveness of the PQS
  • for implementing an effective PQS
  • undertaking an active role in the support, development and implementation of the PQS

Management reviews

Management reviews (clause 1.6) are:

  • a basic quality system element
  • designed to inform the management group of the effectiveness of the PQS
  • important in resolving issues and managing risks by:
    • escalating concerns
    • enabling senior management support

TGA's basic expectations, based on ICH Q10 principles, are that the management review system should include:

  • results and findings of:
    • regulatory inspections
    • audits and other assessments
    • commitments made to regulatory authorities
  • periodic reviews of management quality, which can include:
    • measures of customer satisfaction, such as product quality complaints and recalls
    • conclusions of process performance and product quality monitoring
    • the effectiveness of process and product changes, including those arising from corrective action and preventive actions
  • follow-up actions from previous management reviews

The management review system should also identify appropriate actions, such as:

  • improvements to manufacturing processes and products
  • provision, training and/or realignment of resources
  • capture and dissemination of knowledge
Management review of the Pharmaceutical Quality System

Management are to formally review the PQS on a periodic basis by:

  • measuring the achievement of PQS objectives
  • assessing the performance indicators used to monitor the effectiveness of processes within the PQS, such as:
    • complaint, deviation, corrective and preventative actions (CAPA) and change management processes
    • self-assessment processes, including risk assessments, trending, and audits
    • external assessments, such as regulatory inspections and findings, and customer audits

Monitoring by managers can include both internal and external factors impacting the PQS, such as:

  • emerging regulations, guidance and quality issues
  • innovations that might enhance the PQS
  • changes in business environment and objectives
  • changes in product ownership
Frequency of management reviews

TGA inspectors would generally expect reviews to be conducted at least annually (clause 1.6). However, management reviews may be performed more frequently for:

  • new operations
  • sites that have not previously performed management reviews
  • sites aligned with corporate policies
  • sites where the initial management review identifies a number of issues that require rectification
  • sites with larger and more diverse manufacturing operations

Quality Manual development

Write and maintain a Quality Manual, or equivalent document (clause 1.7).

Describe the PQS in your quality manual, or equivalent, including:

  • the quality policy
  • identification of the PQS processes
  • PQS process sequences, linkages and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting PQS processes in a visual manner
  • management responsibilities within the PQS

Product distribution expectations

When you distribute products:

  • minimise any risk to product quality
  • take account of 'good distribution practice' (GDP) (clause 1.8 (ix))

TGA does not currently inspect the wholesale distribution of therapeutic goods that have been released for supply.

Sponsors and manufacturers have shared responsibility to ensure the quality of medicinal gases are maintained throughout their shelf life, by:

  • ensuring products are stored, distributed and subsequently handled appropriately
  • establishing quality or technical agreements to clearly identify responsibilities, where manufacturer(s) and sponsor are separate entities
Transportation between manufacturing sites

TGA inspections evaluate the transport conditions between sites of manufacture for:

  • Bulk gas
  • packed medicines moved between sites of manufacture

In these circumstances, clause 1.8 (ix) would apply.

Product Quality Reviews (PQRs)

PQRs must be performed for all compressed medicinal gases that are filled on-site.

PQRs are not required for bulk liquefied gases.

There are no requirements to review the stability monitoring programme where expiry dates are not required on the individual batch records or cylinder labels.

Medical air production:

  • is generally:
    • only subject to Part I of the PIC/S Guide to GMP due to the nature of its manufacture
    • is not subject to Part II of the PIC/S Guide to GMP
  • needs to be included in the PQR, where the manufacture starts with the compression of air at the filling site
Supply chain traceability for active substance gases

Manufacturers of medicinal gases should have a clear understanding of:

  • the approved suppliers of active substance gases, for each entity
  • their responsibility in the supply chain between the site of manufacture of the bulk gas and receipt (clause 1.10(i))

Supply chains should:

  • be adequately secure
  • ensure bulk gases are transported under appropriate conditions
  • be mapped
  • have all identified risks managed following the principles of quality risk management
Frequency of PQRs

Perform a full PQR on at least a yearly basis, reviewing all relevant elements of clause 1.10.

It may be acceptable to perform a full PQR on a two yearly basis, when:

  • very few batches of one product are manufactured in one year
  • no manufacturing takes place
  • a scientifically justified rationale is documented

Manufacturers and sponsors are expected to maintain vigilance over elements of clause 1.10 that do not directly relate to manufacturing activities.

For example, during periods where very few, or no, batches of one product are manufactured, recalls and complaints may provide information about products in the market that needs to be recorded in the PQR.

Grouping of products for PQR

Grouping of products is when one PQR is prepared for a group of products. Grouping for the preparation of PQRs is acceptable for medicinal gases.

Batches to be included in a PQR

PQRs are to include all batches for which manufacture:

  • commenced during the current PQR reporting period
  • was terminated, delayed or failed

When grouping is applied, all batches of all products in each group are expected to be included in the PQR.

Shared responsibility for PQRs between manufacturers and the sponsor

Manufacturers and sponsors share responsibility for:

  • preparing the PQR
  • designing and implementing effective systems to ensure that PQR reports and relevant data are supplied, compiled and reviewed
  • establishing technical agreements to clearly define each party's responsibilities in relation to PQRs

Sponsors are also expected to have access to the PQRs, to ensure product compliance with the marketing authorisation.

Quality Risk Management

Quality risk management is mandatory

You must have an operational quality risk management system to ensure that:

  • the evaluation of a risk to product quality is based on a sound, scientific basis and
  • risk assessments are appropriately documented (clauses 1.12 and 1.13)

Annex 20 is voluntary and provides guidance only on quality risk management tools that may be applied by a manufacturer when assessing the risk to product quality.

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