Decentralised Manufacture: UK Guideline of Good Pharmacovigilance Practices
Source: gov.uk (2025-06-10)

Guidance covering various aspects of pharmacovigilance for authorised and unauthorised medicinal products (Specials and the Early Access to Medicines Scheme (EAMS)).

Pharmacovigilance aspects specific to Point of Care and modular manufacture.

Unlike centrally manufactured products, Point of Care (POC) and modular manufacture (MM) medicines are manufactured outside of an established, fixed facility environment and in the case of POC medicines in close proximity to the patient. The manufacturing process is therefore as much a determinant of the product’s quality as the substances within the product, and minor changes or differences in manufacturing steps can affect the product’s quality and subsequently its safety and efficacy. This fundamental complexity creates specific challenges for POC and MM medicines in pharmacovigilance.

Manufacturing variability

Marketing Authorisation Holders (MAHs) of medicinal products make frequent changes to the manufacturing process in the post-authorisation phase. This happens for many reasons, including for example, changes in sourcing material, facilities or regulatory requirements.

Manufacturing changes may by nature potentially be more complex for DM medicines, especially with POC medicines where the manufacturing will be done by individual manufacturing sites and may be subject to slight changes and deviations to processes. It is therefore important that pharmacovigilance considers differences at manufacturing site level as well as at active substance and product level.

Product traceability

As a consequence of the potential for manufacturing variability, a key requirement for pharmacovigilance for DM medicines is the need to ensure continuous product and batch traceability within clinical use and site manufacture.

It is essential that sites can be readily distinguishable so that newly emerging and product specific safety concerns are rapidly detected and evaluated throughout a product’s life cycle.

In many cases the product name and batch information will be included in the product packaging and this information is available to be recorded and reported at all levels in the supply chain from the manufacturing site, which might be at the site of patient administration, to the Control Site. Traceability needs therefore to be fully integrated in different healthcare settings and infrastructure that may vary across DM settings such as the infrastructure for electronic data recording and record linkage. Where batch numbers are not available, other product identifiers must be used to ensure full traceability.

The product name, batch number or other product identifier of a DM product should be recorded at the site of manufacture and given to the administering healthcare professional and provided to the patient.

It is possible that the products may also be highly personalised in the case of some Advanced Therapy Medicinal Products for example and traceability throughout the process is also essential to ensure the right product reaches the right patient.

This guidance covers various aspects of pharmacovigilance for authorised and unauthorised medicinal products (Specials and Early Access to Medicines Scheme, EAMs).

UK Authorised Products

The legal requirements for pharmacovigilance and the good pharmacovigilance practice (GVP) modules1 used alongside the MHRA ‘Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK MAHs and the licensing authority’2 apply to DM products as they do for other authorised medicines and this guidance does not replace any of these. However, as outlined below, DM products are associated with different manufacturing practices and this presents several specific challenges in the conduct of pharmacovigilance activities. This guidance is therefore intended to be read and followed alongside the process related GVP modules and the Exceptions and Modifications document when developing and implementing pharmacovigilance processes for DM products. This guidance describes some specific issues and challenges and will provide guidance on addressing these in the context of standard pharmacovigilance processes described in the GVP modules and Exceptions and Modifications document.

1. Good pharmacovigilance practices (GVP) - European Medicines Agency (EMA) (https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/good-pharmacovigilance-practices-gvp)

2. Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK MAHs and the MHRA (https://www.gov.uk/government/publications/exceptions-and-modifications-to-the-eu-guidance-on-good-pharmacovigilance-practices-that-will-apply-to-uk-mahs-and-the-mhra)

Structures and processes

Risk Management System

All MAAs submitted in the UK after July 2012 should contain a risk management plan (RMP) that must be approved by the MHRA prior to the granting of the MA.

The pharmacovigilance plan within the RMP should include discussion of the healthcare setting the product will be used in and how this may impact the recording and reporting of product name and batch number (or other product identifier). In addition, the pharmacovigilance plan should discuss any activities that may be necessary to support traceability of adverse drug reactions to the product, batch and manufacturing site.

The RMP should describe appropriate pharmacovigilance and risk minimisation activities to address the safety concerns for the product in line with the principles set out in GVP module V and the MHRA Exceptions and Modifications document. Specific measures to follow up the safety and efficacy of the DM product should be described in the RMP as appropriate.

Where additional risk minimisation measures are required, plans for dissemination of the appropriate risk minimisation tools (e.g. educational/safety advice tools) should be appropriate to the DM. Plans should consider engaging the manufacture Control Sites to support dissemination to the relevant recipients.

Management and reporting of adverse reactions

The requirements for the management and reporting of suspected adverse reactions outlined in GVP module VI, alongside the related sections of the Exceptions and Modifications document apply equally to DM products as they do to centrally manufactured products.

When reporting suspected adverse reactions from DM products authorised in the UK, MAHs shall report to the licensing authority all available information on each individual case, including the product name and the batch number (or other product identifier) in line with the Human Medicines Regulations (HMR) 2012 regulation 188. These should continue to be reported in line with the current 15- and 90-day requirements (HMR 2012 regulation 188(1A), (1B) and (1C)). It is therefore important that MAHs ensure appropriate measures are taken to identify the product by batch number or other product identifier (if no batch number is available). MAHs should encourage healthcare professionals to provide patients and/or carers with information on the product name and batch number (or other alternative product identifier) of any DM product administered, regardless of the type of the product, process of manufacture or point of delivery to the patient. Equally, MAHs should encourage healthcare professionals and patients to record information on product names and batch numbers or other product identifier.

In line with GVP module VI, section B.7, ‘the clock for the submission of a valid ICSR starts as soon as the information containing the minimum criteria has been brought to the attention of […] any personnel of the MAH, including medical representatives and contractors’. It would therefore be expected that day 0 starts from the date the ICSR is received at the manufacturing Control Site.

Follow-up procedures should be put in place to obtain the batch number or other product identifier, where this information is not indicated in the initial report.

If the RMP of a DM medicine specifies certain activities to be performed to collect information on defined clinical endpoints, questionnaires may be developed and referred to in the RMP for the follow-up of targeted adverse reactions, in addition to the capture of the product name and batch information.

Periodic Safety Update Reports (PSUR)

Estimated exposure and use patterns

MAHs should be able to obtain data on actual usage of the product. Levels of exposure stratified according to manufacturing site should be provided.

Overview of signal: new, ongoing, or closed & signal and risk evaluation

The guidance within Signal Management (#signal-management) should be applied to the signal evaluation process within PSURs and should be specific to both the product and the active substance. In line with the signal management section, PSURs should specifically evaluate reports and other information which might indicate a risk at a particular manufacturing site.

Signal Management

The requirements for signal management in GVP module IX and the Exceptions and Modifications document equally apply to DM products and to centralised manufactured products. As with all medicinal products, DM medicinal products require continuous pharmacovigilance in order to detect and evaluate potential new risks that may emerge during a product’s life cycle. This is especially important for DM medicines for the reasons described in manufacturing variability (#manufacturing-variability) due to the variability in manufacturing sites that may potentially alter adverse effects of a product and induce clinical consequences.

Signal detection for DM should therefore be specific to the product as well as the active substance.

Processes should be sensitive enough to detect any acute and serious new risks that may emerge at manufacturing site level, for example due to intended or accidental changes in the manufacturing process which may lead to important differences between batches of the same product. Effort should be made to identify any common root causes and identify trends from particular sites.

The frequency of signal detection activities should be conducted at a timeframe and interval period short enough to identify serious safety concerns at manufacturing site level. Product quality information should be taken into consideration within signal detection as well as any site relevant safety information or quality issues for a particular site.

Feedback mechanisms should be in place to alert manufacturing colleagues at the Control Site of any potential signals identified to be associated with a particular manufacturing site to alert them to the possibility of a manufacturing issue at that site.

Additional Monitoring

DM products will be subject to additional monitoring. New products must display the black triangle in product information in line with HMR 2012 regulation 202A.

Safety Communication

Where safety communications are required, communication plans should take into account the DM to ensure that the appropriate target audience is reached and should engage the manufacturing Control Sites where appropriate.

Updates to Product Information

MAHs with DM products must ensure that product information is kept up to date with current scientific knowledge as per HMR 2012 regulation 76. Mechanisms must be in place to ensure that up to date product information contained within the patient information leaflet (PIL) is available to the patient at the time the product is delivered. The implementation timeline of updates to the product information will depend on the type of variation used to make the changes. MAH should refer to the published guidance for full details, but a summary of expectations is provided in this guidance3.

In line with current expectations of the licensing authority for UK authorised products, it is expected that where electronic materials are made available to healthcare professionals and patients, these should be updated within 10 working days of approval by the licensing authority or submission of the change to licensing authority, depending on the variation type. For paper PILs which may be inserted into packs, it is expected that updates will be available within a 3–6-month period following approval or submission of the updated PIL by the licensing authority unless you have been told to introduce the new information early because of safety reasons.

3. Medicines: apply for a variation to your marketing authorisation (https://www.gov.uk/guidance/medicines-apply-for-a-variation-to-your-marketing-authorisation) and Medicines: packaging, labelling and patient information leaflets (https://www.gov.uk/guidance/medicines-packaging-labelling-and-patient-information-leaflets)

Quality Management System

In line with requirements stipulated within GVP module I and corresponding sections within the Exceptions and Modifications document, the MAH should operate a quality management system to support pharmacovigilance processes for DM medicinal products authorised in the UK.

The MAH should consider the quality management provisions in place to ensure the collection and collation of safety information from the manufacturing site to the Control Site and on to the MAH pharmacovigilance department. This should be in line with the processes captured within the DM Master File (DMMF) (https://assets.publishing.service.gov.uk/media/6840207e1d85c6606009cceb/DM_Master_File_Template.docx) which describes mechanisms by the Control Site to gather and report adverse reactions. Relevant controlled documents should be in place to ensure the transfer of safety information to the pharmacovigilance department alongside any contracts and agreements where the MAH has subcontracted tasks to another organisation. These should be in line with requirements specified in GVP module I, section I.C.1.5.

There should be mechanisms in place to have confidence that all notifications are received, and a confirmation and/or reconciliation process should be undertaken. Provisions should also be in place to allow sufficient oversight and consideration of these mechanisms within pharmacovigilance audit risk assessments at strategic, tactical and operational level.

Where an issue/deviation is identified at a site, further investigations should be undertaken to understand whether this is an isolated issue or concurrent across sites and corrective and preventative actions implemented as necessary.

UK Qualified Person for Pharmacovigilance (QPPV)

In line with requirements specified within GVP module I and the UK Exceptions and Modifications document the MAH must have a QPPV appointed for UK authorised products as per section I.C.1.1 who meets the qualifications outlined in I.C.1.2 and whose role complies with the stipulations set out in section I.C.1.3.

When an MAH intends to expand its product portfolio with the addition of DM products, the QPPV should be notified as early as possible in order that the potential impact on the pharmacovigilance system can be assessed, and the system be adapted accordingly.

The QPPV should ensure close links are maintained with the manufacturing function to ensure that any significant issues identified on a product, active substance or site level are communicated so that swift action can be taken to identify any impact on the benefit risk profile of the product or site-specific signals.

UK Pharmacovigilance System Master File (PSMF)

In line with GVP module II, section II.B.4.8 and the corresponding section in the Exceptions and Modifications document, a list of medicinal products covered by the PSMF should be included within the annex to the PSMF. Where products are made under the DM process, this should be made clear within the annex.

Early Access to Medicines Scheme (EAMS)

The following guidance should be read in conjunction with the information to applicants to EAMS4.

4. Early Access to Medicines Scheme - Information for Applicants (https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eams)

Management and reporting of adverse reactions

Regulation 167G of the HMR 2012 sets out the record keeping and adverse drug reaction reporting requirements for medicines that are exempt from the requirement to have a MA under regulation 167E (EAMS). There are new provisions in the HMRs that apply to both MM and POC EAMS medicinal products.

Regulation 167G(1)(b) requires the EAMS scientific opinion holder for MM and POC medicinal products to maintain a record of all adverse drug reactions.

Serious reports are required to be reported to the licensing authority within 15 days of the scientific opinion holder gaining knowledge of the reaction and non-serious reports are required to be reported within 90 days of the scientific opinion holder gaining knowledge of the reaction (HMR regulation 167G(1)(c), (1A) and (1B)).

Adverse drug reactions must be reported to the licensing authority with the product’s batch number or other product identifier if no batch number is available (HMR regulation 167G(1)(c)).

Risk Management System

In accordance with HMR regulation 167G(1)(a), a risk management system must be agreed with the licensing authority and operated by the EAMS scientific opinion holder in accordance with the EAMS risk management plan (RMP).

The same considerations for DM products described in section the UK authorised products risk management system (#risk-management-system) in relation to MAs also apply for the EAMS RMP.

Periodic Reports

In accordance with HMR regulation 167G(1)(e), periodic reports on the use of the EAMS medicinal product must be submitted to MHRA.

EAMS Scientific Opinion holders should be able to obtain data on actual usage of the product. Levels of exposure stratified according to manufacturing site should be provided in the periodic reports.

Specials

Management and reporting of adverse reactions

New provisions in the HMR 2012 apply to both MM and POC specials.

Regulation 170A for MM and 170B for POC medicinal products state that the person who sells or supplies the product must maintain a record of the following information:
- The source from which and the date on which the person obtained the product
- The person to whom and the date on which the sale or supply was made
- The quantity of the sale or supply
- The product’s batch number from which the sale or supply was made, or other product identifier if no batch number is available and
- Details of any reactions to the product sold or supplied of which the person who sells and supplies the product is aware or subsequently becomes aware.
The records above must be kept for at least 5 years from the date on which supply of the product is discontinued (last supplied) and must be made available for inspection by the licensing authority on request.

All serious and non-serious suspected adverse drug reactions to the product are required to be reported to the licensing authority electronically. Serious reports are required to be reported within 15 days of the day the person gained knowledge of the reaction and non-serious reports are required to be reported within 90 days of the day the person gained knowledge of the reaction.

The reports must be submitted within the format and content which is specified within Part 6 of the HMR Schedule 12A. They must also be reported with the batch number or other product identifier if no batch number is available.

Risk Management Plans

In addition to the submission of adverse drug reaction reports, the person is required to set up a risk management system if requested by the licensing authority.

Where a safety concern can be anticipated to be an important risk with the product, there should be due consideration and implementation of measures necessary to minimise that risk. Introduction of a risk management system may be necessary in response to safety information that emerges once the product is in use.