Background

The inclusion of legal tests in SI 2025 No. 87 on Decentralised Manufacture (DM), specific for Point of Care (POC) and Modular Manufacture (MM), stems from comments made in the 2021 public consultation on DM, which stressed the need to avoid confusion between the DM system and the current conventional centralised system of manufacture and supply and to restrict DM to essential use.

The DM designation step is Medicines and Healthcare products Regulatory Agency’s (MHRA) mechanism for evaluating the justifications supplied by applicant organisations who plan to utilise DM. MHRA will evaluate the justifications against either the POC or MM legal tests and in the context of the proposed product, therapeutic indication and patient population. The application for DM designation should occur early in product and process development and may be requested in conjunction with other early engagements with MHRA. This step will provide regulatory clarity and the assurance to innovator organisations to progress the next steps in establishing a DM system.

Guidance

The award of a DM designation indicates that the proposed medicinal product, having been reviewed by MHRA against the legal tests in SI 2025 No. 87, is a candidate for DM either at POC or by MM.

To apply for a DM designation, the applicant should provide a justification of the need for a specific decentralised manufacturing approach against the relevant legal test, which is appropriately supported by quality, and where necessary, clinical data.

The MHRA will review an application for DM designation and may request further information in writing or request a scientific designation meeting, prior to its decision.

Assurance of a satisfactory justification for the use of DM is enabled by the award of a DM designation, in the context of:

A new application for a CTA Application or a Marketing Authorisation (MA).
An amendment to a CTA or variation to a MA
Manufacture of unlicensed medicinal products for human use (commonly described as “specials”) under a Manufacturer Specials (MS) Manufacturing Licence that is, or is intended to be, scoped for DM.

Where DM designation is awarded by the MHRA, a reference for this designation will be provided and this will be confirmed in a letter that can be used as evidence for future regulatory submissions.

There is no mechanism to change the information that supports a DM designation application after the designation has been issued. Where a significant change has been made to the supporting information, a new DM designation should be sought.

Process schematics for each application type are given below.

Clinical Trial Authorisation (CTA)

Designation step	🢚	MIA (IMP) manufacturer’s licence	🢚	CTA application or amendment
Application in the context of a proposed or pre-existing CTA		Compile DMMF Where necessary: - apply for appropriately scoped MIA (IMP) accompanied by DMMF - apply for updated scope to pre-existing MIA (IMP) accompanied by DMMF		Submit with: - DM designation letter - DMMF - appropriately scoped MIA (IMP)

Marketing Authorisation Application (MAA)

Designation step	🢚	MIA manufacturer’s licence	🢚	MIA application or Type II variation to MA
Application in the context of a proposed or pre-existing CTA		Compile DMMF Where necessary: - apply for appropriately scoped MIA (IMP) accompanied by DMMF - apply for updated scope to pre-existing MIA (IMP) accompanied by DMMF		Submit with: - DM designation letter - DMMF - appropriately scoped MIA or confirmation that the application will be withdrawn, should an appropriately-scoped MIA be unavailable at end of procedure

Unlicensed medicine

Designation step	🢚	Manufacturing Specials (MS) manufacturer’s licence
Application in the context of a proposed unlicensed medicine		Compile DMMF Where necessary: - apply for appropriately-scoped MS accompanied by DMMF and DM designation letter - apply for updated scope to pre-existing MS accompanied by DMMF and DM designation letter

When to apply for a DM designation

Applicants are encouraged to apply once data from early stages of the clinical and pharmaceutical development programme indicate that the medicinal product fulfils the relevant DM designation criterion. Early regulatory and other stakeholder engagement is recommended to enable the regulatory flexibilities associated with DM. Inclusion in other MHRA programmes such as the Innovative Licensing and Access Pathway (ILAP) should also be considered.

The MHRA has a legal duty to examine and agree the justification for DM prior to its use and has chosen a DM Designation process to discharge this responsibility. Thus, Applicants should apply for and have confirmation of a DM designation prior to an application for CTA or a MA and prior to the commencement of manufacture and supply of an unlicensed (“Special”) medicine.

Where applicable, DM may be added to a pre-existing CTA or MA by amendment or variation. Confirmation of the DM designation should be provided as part of the application.

The DM designation criteria

There are separate criteria for manufacture at POC and for MM. The relevant criteria that must be fulfilled in order to gain a DM designation, are:

Point of Care: Criterion

The legal definition and criterion for a POC medicinal product is as follows:

A medicinal product that, for reasons relating to method of manufacture, shelf life, constituents or method or route of administration, can only be manufactured at or near the place where the product is to be used or administered.

This can apply to a medicinal product (at any stage of its manufacture) or an intermediate, for which manufacture in close proximity to the patient is essential for clinical or quality reasons, including short shelf-life, method of manufacture, stability or nature of the constituents or route of administration.

The applicant should justify, supported by evidence, that manufacture by traditional means is not possible nor practical. The justification should not be based upon:

convenience either for the manufacturer or the patient
cost minimisation or avoidance Applicants should note that the health technology assessment, commissioning or supply status of a product is not taken into account by the MHRA.

A critical review of the method(s) of manufacture for the proposed medicinal product should be provided, including, where appropriate, an evaluation of the performance of the medicinal product based on quantifiable data (e.g. data on survival, disease progression/relapses, or patient-reported outcomes).

Modular Manufacture: Criterion

The legal definition and criterion for an MM medicinal product is as follows:

A medicinal product that, for reasons relating to deployment, the licensing authority determines it necessary or expedient to be manufactured or assembled in a modular unit.

The applicant should justify, supported by evidence, that manufacture or assembly in modular units is essential for reasons relating to exceptional public health requirements or the expectation that this will deliver significant clinical benefits. The justification may be based on a rationale that scale-out is predicted to be of significant clinical advantage to patients and will address any unmet needs. Such major advantages may be improved efficacy, or similar efficacy with improved overall tolerability. The justification should include direct or indirect comparison to traditional manufacturing models. Applicants should note that the health technology assessment, commissioning or supply status of a product is not taken into account by the MHRA.

Applying for a DM Designation

Applicants seeking a DM designation should complete the DM designation application template in full, indicating how the product fulfils the criterion of designation. Completed forms should be sent electronically to the MHRA Coordinator at Decentralised.Manufacturing@mhra.gov.uk.

The fee for the designation step is that for a scientific advice meeting for quality or where relevant to the justification, quality / clinical development and is detailed in Current MHRA fees. All fees become payable within 14 days following written notice from the MHRA requiring payment of those fees.

The submitted DM designation application will be reviewed by the assessment team and a preliminary internal decision made within a 30-day period. If the application clearly fulfils or fails to fulfil the relevant criterion, the application will be passed to an internal scientific consistency review group with a recommendation for approval or refusal.

If the application is considered to be potentially approvable but further information or discussion is considered to be necessary to confirm the decision, the MHRA will request this information and may also include a request for a designation meeting with the applicant (normally within 60 days of the receipt of the original application). The procedure timeline will be suspended while further information is pending from the Applicant. The scope of the designation meeting is restricted to the potential of the medicinal product to fulfil the DM designation criterion and is expected to last for up to one hour.

If the decision to grant a DM designation is positive, then the applicant will receive a positive designation letter, which will include a unique DM designation number. This number should be included with all future application for DM, including any new or rescoped Manufacturing Licence, a CTA or MA application.

If the application for DM designation is unsuccessful, then this will also be advised by letter explaining why it was considered that the proposal did not fulfil the designation criterion. The applicant may still find it helpful to utilise the MHRA’s scientific advice service and innovation office to help with the ongoing and future development plans. Applicants should note that they may not appeal a DM designation decision.

The Applicant should expect to receive a designation decision:

within 60 days if no additional information and/or a meeting is required
within 90 days should additional information and/or a meeting be required

The MHRA will not publish information about positive or negative DM designations. The MHRA may publish information on the number of designation applications received within a defined period.

Designation letters do not have an expiry period. However, the DM designation is only valid where the proposed product, method of manufacture, therapeutic indication and patient population and clinical landscape remains as described in the justification. If a long period has elapsed between grant of DM designation and DM application, and / or the development of the product has undergone significant change or if the clinical environment justifying the DM designation has changed, then the validity of the DM designation may be reviewed during assessment.

Separate scientific advice meetings can be requested from the MHRA at any stage in the development of the product for other aspects (quality, non-clinical, statistical, pharmacokinetic, efficacy and safety, pharmacovigilance).

Decentralised Manufacture: The designation step