Regulating decentralised manufacturing in the UK – a legal perspective

Governments and the pharmaceutical industry have been considering a novel ways of manufacturing that promises to bring medicinal products, such as their excipients, and medications that are fragile or short-lived, closer to patients.

New UK regulations have established the regulatory framework for ‘decentralised’ manufacturing of medicines in the UK. Although this is happening already, it requires a significant duplication of effort that could arguably stifle progress. Streamlining changes are coming.

In the UK, the Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2024¹ have passed through the UK legislative procedure and will apply from 23 July 2025. They make changes to two UK regulations² governing medicines and clinical trials respectively. The changes answer specific problems relating to advanced therapies and other products for which centralised manufacturing is not suitable, but perhaps the decentralised model is generally better.

Under UK blood regulation³ and human tissue regulation,⁴ licence holders may engage contractors to undertake regulated activities on their behalf. Provided certain requirements are met, those contractors do not themselves need a licence. These hub and spoke models provided inspiration for the creation of the coming UK decentralised manufacturing framework.

In the EU, the EU pharmaceutical package of reform⁵ includes a proposed new Directive,⁶ which will replace the current Medicines Directive (2001/83/EC). That proposed Directive contains a similar regulatory framework for decentralised manufacturing (see prospective Articles 142-153). But the UK framework will arrive first.

The decentralised spectrum

Decentralisation comes in different forms, such as at home, where a person makes a medicine in their home, for example using a consumer 3D printer, as well as point of care, where eg, a cancer medicine is manufactured in a facility located in proximity to where a patient is waiting for treatment, such as in hospital. Then there is the modular option, whereby a self-contained facility has all it needs to make and replicate production of a medicine, so modules are efficiently installed as, when and where they are required to meet demand.

Key concepts

These are the important concepts in the new UK framework:

• Control site – the main manufacturing site, which acts as the hub for regulatory purposes. Other manufacturing sites are subordinate to the control site and do not need their own separate regulatory approvals.
• Master file – the manufacturing dossier in which the main regulatory documents are collected and to which all subordinate sites refer. One file per product. It is kept under review and updated regularly, but the control site has some freedom to update it without requiring approval.

Within the drafting of the new regulation, the concepts of supervision, control of operations, consistency and satisfying the requirements of the master file are repeated. In other words, the control site must have sufficient oversight of the other manufacturing sites (let us call them ‘satellite sites’).

Oversight

This type of system only works if the control site takes full responsibility for the satellite sites. This means robust systems and procedures must be implemented for that purpose. That might be comparatively simple within the same organisation and in relation to sites within a small radius of the control site.

However, the reality of the decentralised model is more likely to look like a large number of sites within a large radius of the control site, covering the territory of an entire legal jurisdiction. It is also likely to involve collections of companies – some related, some not. With that context, it is clear that the major issue to resolve relates to control and reliability. How will the control site be comfortable enough to take the risk of non-compliance and safety issues occurring at satellite sites? The answer is a mix of policies, procedures, staff, technology and contracts.

If a decentralised model is being considered, then detailed governance structures should be designed with a view to achieving robust control of the whole system, accountability and defensible decision making. That should be set out in an internal policy and as a schedule to any relevant contracts. It is important that the control site assumes the responsibility of the regulator.

Access to documents, sites and staff

Each organisation involved in the process, from triggering an order to administering the medicine, should be subject to contractual obligations that require them to:

• follow the requirements of regulation and the master file and comply with the instructions of the control site
• do what is necessary to ensure the quality of the manufactured medicines, including helping the qualified person (QP)
• report issues relating to manufacturing or affecting the patient
• keep records, allow access to those records, and demonstrate their involvement in the process
• permit audits and inspections and be ready to answer questions posed by the control site or the regulator.

For the early period in which the new regulations apply, it is reasonable to expect an extra-vigilant and extra-inquisitive regulator, nervous control sites and very busy QPs. Extra time and resources should therefore be devoted to keeping them all happy.

Safety and site regulation

Safety is a concern. It is easy to imagine that a satellite site could have a slightly different approach to the manufacturing process, staff with different attitudes, different environmental conditions, and different customer or patient needs. Could that lead to safety issues?

To comply with post-market safety monitoring and reporting requirements, control sites must ensure they receive reassurance from satellite sites about strict compliance and transparency. They will also need to require satellite sites to report adverse events promptly and react to instructions from the control site when safety issues occur.

Developing point-of-care CAR T manufacturing

Some satellite sites will be more prone to safety and site regulatory issues than others and for some the normal approach taken in large centralised facilities will not be suitable. It is advisable to initiate designing and testing measures early and work out what that additional regulation means in the decentralised context.

If a contractor is involved in a decentralised manufacturing procedure, consider potential disaster scenarios, such as injuries, quality problems, data loss, security incidents, regulatory breaches and property damage. Then use that thinking to inform discussions about liability limits and exclusions, indemnities and insurance.

Technology

For the technical operation of a web of sites, systems must enable them to all share data and communicate with each other. And, given the risks associated with human interpretation, variation (with respect to gaps in standard operating procedures) and error, manufacturers should have detailed conversations with technology vendors or in-house experts about remote monitoring and automation.

Problems relating to technology may result in regulatory breaches, injury, losses relating to diminished sales, and damaged reputation. Start the difficult conversations about liability early and strengthen contract provisions concerning implementation, acceptance, service levels and support.

Super QPs

In large organisations, a qualified person (QP) may be well accustomed to overseeing multiple sites and complex supplier relationships. But if they are required to take responsibility for the satellite sites, of which there may be many, will their challenging role become more difficult? Surely, in many decentralised scenarios it will.

There is some recognition in the new UK regulations that normal QP releases would not be possible in certain scenarios. Otherwise, the QP role is essentially multiplied, and thus QPs are advised to start checking whether they will have the assistance they need (and if their insurance policies are still fit for purpose). The businesses implementing decentralised manufacturing operations should review policies and contracts and consult with the QP as to whether they should secure requisite help internally and/or externally.

Knowledge arising from manufacturing – improvements

If a manufacturing process is not thoroughly tried and tested, it is possible that a person carrying out that process could develop an improvement that makes a big difference to the success of the product being manufactured. That is a risk for the product owner or the owner of manufacturing technology since the person that owns that improvement may decide to prevent use of it or even offer it to a competitor. The context of decentralised manufacturing may increase this risk due to the number of sites involved and the chance of local variations in the finer details of the process used at those sites. It is thus advisable to carefully check the intellectual property provisions of relevant contracts to ensure that blocking technology does not put the business at risk.

Decentralised diagnostics

It is useful to visualise a patient’s journey through the (hypothetical) decentralised system: Patient feels sick; gets tested; receives diagnosis; obtains prescription; doctor has medicine manufactured locally; patient attends local hospital or treatment centre; medicine is administered to the patient. Considering this journey, the diagnostic test could (and should) happen locally too. In January 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) published guidance⁷ on using in vitro diagnostic devices at the point of care and, also starting in 2021, NHS England has implemented a Community Diagnostic Centre (CDC) programme⁸ with 170 approved CDC sites (at the time of writing).

There will be opportunities to reach out and start discussions about linking diagnostic and manufacturing operations, premises, equipment and technologies. Start with a confidentiality agreement and then see where it goes!

Relationships

For a system involving many different stakeholders and users in many different locations, there are key relationships to build and maintain. For example, clinicians and hospitals. Depending on the degree of decentralisation, it may be critical to have well-trained individuals on site who collaborate with manufacturers. If the manufacturing takes place on that site, then rights to use facilities and intellectual property will need to be negotiated, and a robust system of oversight (possibly across organisations) will be needed.

Secondly, marketing authorisation holders (MAH) have a lot at stake in a decentralised system and will need to rely heavily on all those organisations and individuals that are closer to the patient. The manufacturer will want the MAA to provide sufficient information to ensure the master file is consistent with the marketing authorization, highlighting the critical importance of an efficient flow of information.

Sustainability

At a basic level, fewer miles equals fewer tons of CO₂. This suggests that decentralised manufacturing must be better for the planet as the medicine is closer to the patient. However, the reality may be different. A sprawling network of sites will require input materials to be delivered to them and each site will produce waste and, potentially, effluent. Serious consideration must therefore be given to whether decentralised manufacturing is sustainable when compared to the current system.

The NHS is working towards being Net Zero by 2050 and that agenda is being aggressively pursued. All those who touch the NHS supply chain are affected and will be challenged to demonstrate their green credentials. It is a complex task for most businesses to collect data and confidently calculate their carbon footprint. Serious questions remain regarding the impact of decentralised manufacturing approaches on the road to Net Zero for any business in the medicines supply chain and on the task of reporting up that chain.

While lawyers do not have the answers to these questions, one thing is certain: the laws relating to sustainability, and the impact those laws have as the requirements they impose flow down supply chains, are likely to get tougher.

What’s next?

With the eyes of other regulators (including the EMA) watching, the MHRA is likely to be very sensitive about strict compliance and transparency. It will also want the system to be seen to work well. But, even if the regulation works as it should, attitudes and infrastructure need to be made ready for decentralised manufacturing. In this sense, the conversation has started but it needs momentum, which ought to come from patients, patient groups, clinicians, hospitals, NHS procurement and commissioning, those responsible for NHS facilities, and local authorities, as well as MAHs and manufacturers.

The rest of the world will be interested to see how decentralised manufacturing works in practice and whether there is scope for fixing some of the supply issues around the world. For those in the lead, there is an opportunity to improve global health equity and better prepare for major health incidents.

References

1. The Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2024. [Internet] UK Government. Available from: https://www.legislation.gov.uk/ukdsi/2024/9780348264579/contents
2. Human Medicines Regulations 2012 and Medicines for Human Use (Clinical Trials) Regulations 2004.
3. Under the Blood Safety and Quality Regulations 2005.
4. Under the Human Tissue Act 2004.
5. Revision Of The EU’s Basic Pharmaceutical Legislation, Including Medicines For Children And For Rare Diseases. [Internet] European Parliament. Available from: https://www.europarl.europa.eu/legislative-train/theme-promoting-our-european-way-of-life/file-revision-of-the-pharmaceutical-legislation
6. Proposal for a DIRECTIVE OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on The Union Code Relating To Medicinal Products For Human Use, And Repealing Directive 2001/83/EC And Directive 2009/35/EC.
7. In Vitro Diagnostic Point-Of-Care Test Devices. [Internet] UK Government. Available from: https://www.gov.uk/government/publications/in-vitro-diagnostic-point-of-care-test-devices
8. Community Diagnostic Centres – Guidance For Planning, Design And Implementation. [Internet] NHS England. Available from: https://www.england.nhs.uk/long-read/community-diagnostic-centres/