PIC/S Annex 6 revision: Medicinal gases under scrutiny
Why computerised systems, validation, and “state of the art” expectations now matter more than ever
Medicinal gases are gases that fulfil the definition of a medicinal product and are regulated as such under PIC/S GMP Annex 6. They include products such as oxygen, medical air, nitrous oxide, nitrogen, carbon dioxide, gaseous mixtures and anaesthetics, when used as medicines. Medicinal gases are often invisible to patients, yet indispensable to modern healthcare. These products underpin routine clinical care, surgery, and emergency medicine and they have unique risks as, unlike many other medicinal products, they are frequently administered continuously, embedded directly into hospital infrastructure, and relied upon in time‑critical scenarios.
When something goes wrong, the consequences can be immediate and critical. Against this backdrop, and because of evolving manufacturing technologies and the increasing use of associated computerised systems, medicinal gases are once again firmly in regulatory focus.
In early 2026, the Pharmaceutical Inspection Co‑operation Scheme (PIC/S), via regulators including the Therapeutic Goods Administration (TGA), opened a public consultation on a concept paper proposing revisions to Annex 6 – Manufacture of Medicinal Gases. The stated intent is a targeted update to reflect current industry practices, including the increased use of new technologies and computerised systems.
While the proposed revision is described as ‘limited’, the signals it sends are clear: expectations around automation, validation, governance, and technical oversight of medicinal gas manufacturing systems are rising.
Why medicinal gases are uniquely challenging
Medicinal gases are regulated as finished products, but in practice they are often managed like critical utilities. They are:
- Produced and supplied continuously
- Distributed via fixed infrastructure (pipelines, tanks, manifolds)
- Administered directly to patients, sometimes with limited downstream testing
- Often essential to life‑support and emergency care
From a patient safety perspective, this creates a unique risk profile. Errors in gas composition, pressure, or labelling can be difficult to detect but can result in immediate harm. Supply interruptions can escalate rapidly into clinical incidents. During the COVID‑19 pandemic, global oxygen shortages highlighted just how vulnerable these systems can be when demand surges or supply chains fail.
Good practice therefore, requires medicinal gases to be managed in a similar manner applied to GMP‑critical utilities, such as water for injection or clean steam, but with an appreciation of their unique risks to patient safety, even where the manufacturing process itself appears straightforward.
Medicinal gases may be chemically simple, but the systems that produce and deliver them are not.
Why Annex 6 is being revisited now
Annex 6 of the GMP Guide has not undergone a major revision since 2010. Since then, the way medicinal gases are manufactured, monitored, and supplied has evolved significantly.
The Annex 6 concept paper highlights significant drivers for change:
- Advances in automation and control systems
- Widespread use of programmable logic controllers (PLCs) and supervisory control and data acquisition (SCADA) platforms
- Modern container and valve technologies designed to minimise the risk of mix‑ups and contamination
- Lessons learned from recent global supply disruptions
What the Annex 6 concept paper signals
The concept paper does not propose a wholesale rewrite of Annex 6 but rather a targeted modernisation, focused on aligning regulatory text with current practice.
Key themes include:
- Recognition of closed, positively-pressurised gas manufacturing systems
- Updated expectations for container and valve technologies
- Greater clarity around inspection and control of integrated regulator and flowmeter valves
- Explicit acknowledgement of computerised systems in gas manufacturing and distribution
Annex 6 Medicinal Gases in Consultation
Download your free review of the anticipated changes to Annex 6
Automation in medicinal gas systems: PLC and SCADA in focus
Modern medicinal gas operations rely heavily on programmable logic controllers (PLCs) and supervisory control and data acquisition (SCADA) systems. These systems manage:
- Gas generation and purification
- Pressure regulation and flow control
- Alarm management and interlocks
- Distribution across bulk tanks, pipelines, and hospital interfaces
- Data logging and trending
From an operational perspective, this automation improves consistency, efficiency, and safety. From a GMP perspective, however, it has introduced new risks that must be actively managed.
These systems are directly responsible for maintaining product quality and patient safety.
PLC and SCADA validation expectations of Annex 6
Although Annex 6 itself may not prescribe detailed computerised system validation requirements, inspectors expect medicinal gas automation to meet broader GMP expectations for computerised systems.
In practice, this means a lifecycle‑based validation approach, proportionate to risk, as detailed in Annex 11 Computerised Systems.
Alarm management: a growing inspection focus
Alarm systems are central to automated gas operations, yet they are also a frequent source of inspection findings.
Common issues include:
- Excessive or poorly rationalised alarms
- Lack of documented alarm testing
- Unclear escalation and response procedures
- Over‑reliance on contractor intervention without adequate oversight
Good practice approaches we commonly see include:
- Alarm rationalisation exercises to identify GMP‑critical alarms
- Proceduralised periodic alarm testing
- Clear definition of who responds to alarms, and within what timeframe
- Training records demonstrating that personnel understand alarm significance
Data integrity and automation
Where PLC and SCADA systems generate or store GMP‑relevant data, data integrity principles apply.
This does not mean every control system must look like a laboratory information management system, however, inspectors increasingly expect manufacturers to understand:
- What data is generated
- How it is stored
- Who can access or modify it
- How changes are controlled and recorded
Even where systems are largely engineering‑driven, quality oversight remains essential.
Annex 6 alignment with Annex 15: qualification and validation
The Annex 6 concept paper consultation was run in parallel with a concept paper proposing updates to Annex 15 – Qualification and Validation. Taken together, these revisions reinforce a consistent regulatory message: qualification and validation expectations apply across all GMP‑critical systems, including automated infrastructure.
From a planning perspective, this alignment matters.
Manufacturers should expect inspectors to look for:
- Clear qualification strategies covering gas plants, tanks, pipelines, and control systems
- Risk‑based justification for validation scope and depth
- Integration of engineering activities with quality systems
- Evidence that changes are assessed holistically, not in isolation
This is where Annex 15 principles provide a useful framework for medicinal gas manufacturing operations, even if not explicitly referenced in Annex 6.
Supplier qualification and outsourcing: shared responsibility, retained accountability
Medicinal gas supply chains are often highly outsourced. Bulk gas suppliers, cylinder filling contractors, transport providers, and on‑site service organisations may all play a role.
However, regulatory responsibility does not disappear when activities are outsourced.
Good practice governance models typically include:
- Clear delineation of GMP responsibilities in contracts
- Risk‑based supplier qualification and periodic review
- Defined oversight of contractor activities, including maintenance and testing
- Integrated deviation and change management processes
Key reminder: Regulators will look at how oversight works in practice, not just what the contract says.
When small deviations become serious incidents
Medicinal gas recalls are relatively uncommon, but when they occur they often stem from seemingly minor failures:
- Labelling errors during cylinder changeover
- Incorrect connections or valve incompatibility
- Undetected pressure or flow deviations
- Inadequate segregation between gases
- Lack of traceability of re-useable cylinders
These events reinforce why regulators continue to treat medicinal gases as high‑risk products, even where manufacturing processes are mature and well‑understood.
What inspectors are likely to ask – contractor focus
Inspectors assessing medicinal gas operations increasingly ask questions such as:
- How are PLC and SCADA alarms validated and periodically tested?
- How are changes to control logic assessed, approved, and documented?
- How is data integrity assured for automated systems?
- How are contractors trained, qualified, and supervised?
- How are deviations escalated across organisational boundaries?
- Who has access to the control systems and how is that controlled?
Being able to answer these questions clearly, with evidence, is often the difference between a smooth inspection and a difficult one.
Preparing now: practical steps while Annex 6 is being revised
While the final wording of a revised Annex 6 may still be some time away, organisations can act now to minimise the impact to their operations.
Practical preparation activities include:
- Mapping medicinal gas manufacturing systems and interfaces end‑to‑end
- Reviewing validation status of generation, storage, and control systems
- Assessing computerised system governance against GMP expectations
- Stress‑testing supplier oversight arrangements
- Updating risk assessments to explicitly address automation and changeover risks
Many organisations find value in approaching this as a continuous improvement exercise, rather than a one‑off compliance project, aligning with broader GMP maturity principles.
PharmOut Services & Training
PharmOut consultants support medicinal gas manufacturers and healthcare organisations with:
- GMP advisory services for medicinal gases
- Computerised systems validation (CSV)
- Critical equipment and utilities qualification
- Audit readiness and inspection support
We work closely with engineering, quality, and operations teams to ensure automation enhances GMP compliance.
PharmOut also delivers targeted training on lifecycle validation, risk‑based decision‑making and inspection readiness. Explore elearning and public courses via onlinegmptraining.com, or contact us via the website or via email to tailor workshops to your needs.
Frequently Asked Questions (FAQ)
Annex 6 provides GMP guidance for the manufacture of medicinal gases, and it’s being updated to reflect current industry practice and modern technologies. The 2026 concept paper signals increased regulatory attention on automated systems and oversight.
Yes. Where PLC/SCADA performs GMP‑critical control, monitoring, alarms, or data capture, inspectors typically expect lifecycle, risk‑based validation aligned with Annex 11 principles. The focus is on demonstrating the system is fit for intended use and remains in a controlled state.
Expect questions on alarm testing and rationalisation, change control for control logic, user access management, and how deviations are detected and escalated. Inspectors will usually want evidence that quality oversight is effective, not just that the system “runs.”
If PLC/SCADA generates or stores GMP‑relevant data, you need to understand what’s recorded, who can change it, and how changes are tracked. Controls should be proportionate to risk but strong enough to prevent undocumented or unauthorised alterations.
Start by mapping end‑to‑end systems and interfaces, confirming qualification/validation status, and reviewing governance for alarms, access, and change control. Also test supplier and contractor oversight arrangements, because accountability remains with the manufacturer even when work is outsourced.
