Manufacturing Licence applications and Inspection approach

The Control Site must be in the UK and hold the appropriate MHRA issued manufacturing licence, following the standard approach as detailed in Apply for manufacturer or wholesaler of medicines licences.

Note 1: While Section 10 has not been amended to prohibit the dispensing of point-of-care (POC) or modular manufacturing (MM) medicines, any such activity must still occur under appropriate circumstances, ensuring patient safety and compliance with professional standards. See also 2.3.14 of Human medicines Modular Manufacture and Point of Care regulations 2025 .

Note 2: DM legislation has not impacted the definition of manufacturing vs assembly vs reconstitution or preparation for administration.

The application, or variation to an existing licence, must be submitted to support each product dosage form specific DM activity. This is a new categorisation added to the application process. As with any new application or variation, this will be assessed and is expected to trigger an inspection on the principles of Quality Risk Management. The application should include an applicable completed DMMF (referred to as the dossier within the Human Medicines (Amendment) (Modular Manufacture and Point of Care) Regulations 2025).

During inspection, with regards to the specifics for DM processes, the Control Site will be expected to demonstrate the following as a minimum (this list is not exhaustive):

Procedures in place to support the following:
- Management of DM control strategy
- Generation and management of DMMFs, including designation and annual reporting processes
- Onboarding (initiation), suspending or pausing (as applicable) and cessation of remote sites. Mechanisms must be in place for the Control Site to provide timely, clear and unambiguous information on the status of each remote site to each site.
- Ongoing oversight of activities and performance of remote sites including the integrity of data.
- Provision of equipment together with oversight of maintenance and calibration.
- Provision of supplies and components to remote sites as necessary.
Training programme, initial and ongoing, for remote site staff (if not allocated from a pool of staff at the Control Site)
Specific product release procedures for DM products, including but not limited to:
- Immediate use release via on-site personnel for POC products (not applicable for MM products)
- Qualified Person certification or Named QC oversight (as applicable)
A completed DMMF for a product that has undergone DM designation assessment.
- Note: The DMMF detail is described in a separate guidance document
Evidence that manufacturing and assembly is under appropriate control so that the DM medicinal product consistently satisfies the requirements in the DMMF when manufactured at remote units.

Note: these are the DM specifics in addition to the routine, existing requirements for any Manufacturing licence holder.

Routine inspections will occur of the Control Site, and each inspection will also consider the requirement to physically inspect a representative selection of current remote sites, ideally in operation where possible or simulating processes.

Note: Each remote site is not required to be named on the Manufacturers licence, as this will be managed by the Control Site via the DMMF. The Control Site is required to provide an annual update relating to each DMMF, which should include a summary of all changes, regardless of any prior notifications throughout the year. (Note: this is separate from and does not replace MAA / CTA variation requirements).

Pharmaceutical Quality Systems (PQS).

Control Sites have legally prescribed activities and duties to create and maintain a state of control across all sites within the organisation and where the Control Strategy approach described in ICH Q8 will be valuable. In establishing and maintaining a state of control, the application of Quality Risk Management (QRM) principles should be used to evaluate the risks to quality across the size and complexity of the structure and activities of a DM organisation. These should take account a range of factors, these may include, but are not limited to:

Geographical separation of sites.
The location of some or all DM sites being on or hosted within the premises of other organisations.
The establishment of suitable technical agreements between parties.
A communication system between the Control Site and the remote sites and, where required, between the remote sites (with the Control Site in copy for awareness for control purposes). The components of such a system, including their degree of sophistication and integrity of the data, should be related to the information requirements that system is required to transmit.
Minimum criteria for qualifications and experience of the designated person responsible for release at each remote site and an assessment of their competence (by the Control Site QP or named QC as applicable).
Assessment of the product via manufacturing procedures, evaluation of significant deviations or non-conformances, supply requirements and potential pharmacovigilance signals.
The arrangements between the DM Control Site activities and remote activities which may include a range of interactions with the local host Quality System for the remote site.
Changes, which may be relatively frequent, to the number and locations of DM remote sites. This must cover the lifecycle of sites from establishment of new sites through to decommissioning of sites.

Evaluation of significant deviations or non-conformances should include:

Factors that will facilitate the differentiation of manufacturing issues at a site or sites from issues that relate to the product, and which will form part of signal detection and reporting through the pharmacovigilance system.
Systems should be designed to detect significant new risks, based on product and process knowledge. The investigation should seek to determine whether issues are related to specific sites or more generally to procedures or the product.
Assessment of any accidental changes in the manufacturing process which may lead to important differences between batches of the same product.

Manufacturing activities must only occur at sites that are ‘active’ in the DMMF, similarly manufacture must not occur at DM sites that have been decommissioned by the organisation or suspended by MHRA. The operational status, or otherwise, of manufacturing sites should be documented and be clear to personnel.

The assurance of consistency in the manufacturing operation between sites, and therefore the comparability of product, should be a particular focus by the Control Site. This is built on in-depth product and process knowledge, including sources of variability and identification of Critical Process Parameters (CPPs) and associated Critical Quality Attributes. The range of GMP considerations that form the basis of this uniformity between sites include, but are not limited to:

consistent application of PQS elements including appropriate change control,
well-defined manufacturing process with its associated process controls,
the degree of automation of process equipment,
training and competency assessment of operators
training and competency assessment of releasing personnel (for POC)
equipment and software version control, including qualification and calibration
starting and raw material controls,
process qualification,
packaging and labelling controls (including blinding as appropriate for Investigational Medicinal Products (IMPs))
analytical data of batches manufactured at different sites.

Substances of human origin (SoHO) used as starting materials

The donation and procurement of substances of human origin (which includes blood, blood components, tissue and cells) used as starting materials, and any associated donor testing, must be carried out in accordance with relevant regulations, including with respect to licensing.

Manufacturers are advised to contact the relevant regulator (e.g. the Human Tissue Authority (HTA) and MHRA) to discuss appropriate licensing models for any planned decentralised manufacturing or for guidance about the application of SoHO licensing exemptions.

Where licensing exemptions exist, such as when autologous tissues and cells are used within the same surgical procedure, these should be clearly stated in the PQS. In such situations, the principles of quality risk management should be followed to ensure the quality of the substances of human origin, and therefore the medicinal product, is maintained. These include that:

the evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and that
the level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

Elements to consider in assessing the level of risk include, but are not limited to, whether the substance of human origin is removed from the field of surgical or medical intervention for further manufacturing. Where the substance of human origin is removed, other considerations include traceability, the distance of travel from the field of surgical or medical intervention to the manufacturing unit and associated controls, the duration of the manufacturing process, the need or otherwise for storage, and the processes required during the return of the medicinal product.

Shared facilities

For POC products, it is likely that manufacturing facilities will be either be shared or in close proximity to other activities and their personnel will be present. The effects of adjacent activities should be taken into account during the assessment of the suitability of the premises. Measures should be taken, technical and / or organisational, in order to prevent the risk of cross-contamination and the entry of non-manufacturing staff or, where this is not possible, to mitigate any adverse effect on the medicinal product manufacture from the other activities or staff.

Evidence should be recorded within batch records of applicable line clearance of defined working areas, prior to processing.

Product Release for Products with short shelf lives (POC)

Local release procedures, including clarification of the designated person responsible for release for administration, are required for such products with clear links to the certification process.

Some DM (POC) products may have to be supplied and administered on the basis of an assessment of batch documentation and CPPs either before analytical tests have been performed or in place of analytical tests. Activities by designated persons are being undertaken on behalf of the Qualified Person or Named QC and remain under their remit.

Where authorised, RTRT, a combination of in-process monitoring and controls may provide, when authorized, a substitute for end-product testing as part of the batch release decision. This is based on QRM principles, product knowledge and process understanding and information collected during the manufacturing process.

Product release may include the following stages:

At the site of manufacture prior to making a decision on the supply of product for administration: an assessment by a designated person of batch processing records, which should also cover the following:
- CPPs (as appropriate to the phase of product development),
- Production conditions including results from environmental and facility monitoring (where available)
- Analytical testing performed to that time,

Note: The revised EU/PIC/S Annex 1 allows alternative, real-time, monitoring methods and data to be considered as part of the release decision for short shelf-life products.

This designated person should be independent, such that they are separate from those involved in the manufacture of the product and there is also a need to avoid other conflicts of interest e.g. clinical care of the patient.

Post Administration: Final assessment by the Qualified Person or by a Releasing Officer under an MS licence of the following:
- The full batch records and facility records
- Any final analytical data,
- Confirmation that all deviations from normal procedures are documented, justified and appropriately released prior to documented certification

These evaluations should occur as soon as possible after product administration when all available data is available, to avoid any delays in assessing the final status.

Where out of specification (OOS) test results are obtained or following any production process anomaly, a procedure should be in place to describe the measures to be taken. Factors to consider should include (but not limited to):

Liaison with clinical staff with regards to POC products under an MS licence
Rejection of POC product where CTA or MAA criteria are not fulfilled

Such events should be fully investigated and the relevant corrective and preventive actions taken to prevent recurrence documented.

Note: due to the immediacy between manufacture and administration, it is not anticipated that OOS POC Advanced Therapy Medicinal Products (ATMPs or ATIMPs) would be administered. This is due to the requirements for the written justification from the parties involved. Note: The existing approach for any OOS ATMP or ATIMPs would however be considered for MM products.

Where product fails to conform to requirements during post-administration, this should be assessed and treated as a recall situation in line with existing processes for products conditionally released.

Product Release for Modular Manufacturing (MM) Products

Product release for MM products should follow the routine approach for medicinal products. The MM product batch should be assessed, certified and released as in a traditional manufacturing site.

Product Reviews

Continuous learning through data collection and analysis over the life cycle of a product is important and should be part of the PQS. Manufacturers should have systems to ensure that opportunities to improve product quality and/or consistency are identified and appropriately acted upon. With advances in technology, certain data trends, intrinsic to a currently acceptable process, may be observed.

Where trends indicate that product Critical Quality Attributes may fall outside of specifications or registered values, the appropriate regulatory authority/ies should be consulted in a timely manner. Any adverse trends indicating a change in the state of control should be followed up appropriately.

Reference and retention samples

The plan for taking POC product sampling should be documented with adaptions for the product and process taking into account the risks and practical limitations that exist e.g. limited shelf-life and quantity of product. Mitigation measures, with appropriate justifications, should be included in the sampling strategy. Where the approach is product specific, this should be included or referenced in the DMMF.

Where full retention samples are not possible, then representative samples of packaging and labelling or clear photographic evidence should be retained.

Modular manufacturing processes should follow the appropriate expectations as in a traditional manufacturing site.

Physical samples should be accessible to or overseen by the Control Site, with storage defined in technical agreements as applicable.

Named individuals on Manufacturing licences

The range and geographic separation of DM sites places additional challenges on availability, hence additional mechanisms should be considered to meet this requirement.

Given the relative frequency of changes to sites and the potential impact of these changes on the consistency of product manufacture and quality, key personnel including the Head of Production, Qualified Person or Named QC on an MS licence should be involved in the establishment of new sites, the on-going suitability of sites and decisions to decommission sites.

The Qualified Person remains responsible for the release of all IMP or commercial DM products.

QP certification for MM products should occur prior to distribution or administration in line with the standard approach for fixed facilities.
QP release registers / logs should clearly identify which remote site was utilised for each batch.
Where separate logs are in place for each MM unit, these should be accessible to the Control Site.

The Named Quality Controller in MS licences may delegate release as in MHRA Guidance Note 14 for Specials Manufacturers, however a separate oversight, approval and tracking mechanism for DM releasing officers should be in place.

Applications to name individuals as QP or QC onto Manufacturing licences should include justification for the named person with regards to dosage form as routinely required, and for all named personnel there should also be demonstrated an understanding of the oversight of activities undertaken at decentralised sites of manufacture.

Home based manufacturing considerations

Manufacturing equipment used should contribute to the consistency of the DM products. Where possible, consideration should be given for the equipment to:

remote monitoring, potential by linking into the communication system between the Control Site and the remote sites.
for such information to contribute to the product releases process.

The suitability for use of equipment used in home-based manufacturing should be evaluated taking into consideration the range of scenarios of use including the skill level and ability of the operators. This includes the provision of training to the operator(s) and an assessment of the proficiency of the operator(s) in the correct use of the equipment.

Decentralised manufacture: UK Guideline on Good Manufacturing Practice (GMP)