On 21 October 2024, the Medicines and Healthcare products Regulatory Agency (MHRA) announced that the UK will be the first country in the world to introduce a tailored framework for the manufacture of innovative medicines at or close to the location where a patient receives care.
A new statutory instrument was laid before the UK parliament to amend the Human Medicines Regulations 2012 and the Medicines for Human Use (Clinical Trials) Regulations 2004, to provide a new regulatory framework to support the manufacture and supply of these innovative products. This includes:
- products with a very short shelf life and highly personalised medicines that mean they have to be manufactured close to the place where they are administered; known as Point of Care, or POC, products. This often applies to advanced therapy medicinal products (ATMPs), but could also be technologies such as 3D printing.
- products that are manufactured in a self-contained modular unit, to enable deployment from that site to other locations; known as Module Manufacture, or MM, products.
This new framework follows a consultation in 2021, discussed in a previous blog post. The consultation received overwhelming support, and 91% of responders agreed with the need for a new regulatory framework. At present, there is no specific framework that covers decentralised manufacturing of medicines in the UK, but as products become more innovative, and more personalised to the patient, the need for change has increased. At present, any on-site manufacturing has to rely on the hospital having obtained the necessary licences and having put in place the required quality, safety and traceability standards under the general framework. This leads to practical – and contractual – difficulties between the company and hospital sites.
The new framework seeks to provide the necessary regulatory oversight to ensure that POC and MM products have appropriate quality, safety, and efficacy attributes, whilst allowing increasing numbers of patients to benefit from these innovative products. According to the MHRA, the proposed regulation ensures that POC and MM products can be more easily made in or near a hospital setting and can get to the patients who need them safely and more quickly.
Manufacturer's Obligations
The structure of the new framework is centred on having a Control Site, which will be the only location named on the manufacturer's licence. This Control Site will oversee all aspects of the manufacturing system, including the individual manufacturing locations and their activities, and be named on clinical trial and marketing authorisation applications.
The holder of the manufacturer's licence will be required to maintain a POC or MM master file (which may include an investigational product master file if the product is being manufactured for a clinical trial). For POC manufacture, the POC master file will name all of the individual POC manufacturing sites, and the relevant authorisation and supervision mechanisms for those sites. Similarly, for MM manufacture, the master file must set out the relevant modular units.
Some of the key obligations on the manufacturer's licence holder are:
- to ensure that the medicinal products specified in the licence are not handled, controlled, stored or distributed on any premises other than the Control Site and those specified in the master file
- to ensure the information contained in the master file is kept up to date and is consistent with the UK marketing authorisation for the product (where relevant)
- to record and report all suspected adverse reactions to the marketing authorisation holder or sponsor
To apply for a manufacturer's licence for POC or MM products, the applicant must supply detailed information about the product and the sites at which it will be manufactured and assembled, including:
- the location of each site at which the manufacturing and the operations are to take place
- a description of the process by which the licence holder will approve and suspend new sites
- a description of the various processes at each site, including manufacturing and assembly, in addition to details of the supervision arrangements by the licence holder
- contact details for people at each site who are to be contacted in respect of manufacturing, assembly and quality operations under the licence
- a description of the processes by which the licence holder will review and amend the master file
Impact on Marketing Authorisation Holders and Clinical Trial Applicants
Marketing authorisation holders for medicinal products that will be manufactured using POC or MM methods must supply information to the manufacturer's licence holder so that the manufacturer can ensure the licence and master file are consistent with the marketing authorisation at all times.
Marketing authorisation applicants or applicants for clinical trial authorisations involving such products must supply the MHRA with a copy of the master file and provide information regarding the measures put in place to ensure the follow-up of the efficacy of the product and of any adverse reactions to the product. Under good manufacturing practice, the marketing authorisation holder has various obligations in relation to manufacture, and the two authorisation holders will need to ensure appropriate processes, information sharing and oversight to ensure both sets of obligations are met.
Next Steps
The timing of the proposal is not clear, and the government has a long list of legislative priorities for its first year. However, the amendments could come into force in 2025. In the meantime, the MHRA is developing supporting guidance to aid the interpretation of the new regulations ahead of the legislation coming into force.
Position in the EU
Only high-level general considerations are set out in guidance from the European Commission and European Medicines Agency in relation to decentralised manufacturing and the manufacturing of ATMPs at POC. Therefore, as with the current position in the UK, while decentralised manufacturing methods are permitted, few companies operate in this area due to the difficulties in navigating national legislation and the lack of a clear EU framework and guidance.
However, the European Commission's proposal for reform of the EU regulatory framework for medicinal products, published in April 2023, and which is currently pending adoption by the Council after approval by the Parliament in April 2024, contains proposals concerning the decentralised manufacturing of ATMPs. Similar to the UK proposed framework, a key role will be played by a central manufacturing site that will be responsible for oversight of the decentralised sites. According to the proposal, a manufacturer's licence would be required only for the central manufacturing site, subject to specific conditions.
The proposal, however, only provides high-level principles on the interactions between central and decentralised sites, and detailed guidance will be essential for companies to implement such manufacturing schemes. Further, it is still unclear to what extent the proposed legislation will be approved and/or modified by the Council and by when the final legislation will be adopted.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.
