Defective Medicinal Products and Recall Management Guidance – The main concerns with regard to possible defects of medicinal products and the substances used in their manufacture or packaging. It applies to all medicinal products, both licensed and unlicensed products. It may be difficult to differentiate between a defect, or errors and adverse drug reactions, as a result the initial assessment of a suspected defective medicinal product should be performed by an appropriately qualified and experienced healthcare professional, who should decide on appropriate classification of the “incident” and issue a referral to the appropriate organisation and/or regulatory body if required.
Medicines and Healthcare products Regulatory Agency (MHRA) department who handle defective medicinal products, the Defective Medicines Report Centre (DMRC). It is the role of the DMRC to minimise patient risks which arise as a result of the distribution of defective medicines by providing an emergency assessment and communication system within the medicinal product supply and distribution chain. This is achieved by receipt and assessment of suspected reports of defective medicinal products for human use. These are then followed up with advice and monitoring of actions required by the responsible Licence Holder and communication of details of action to relevant parties.
If a recall is required for a medicinal product, the relevant Licence Holder is consulted for a decision and it is the responsibility of the Licence Holder’s to ensure that a recall is carried out effectively throughout the distribution chain. The DMRC will issue a Recall Notification to support action taken by the Licence Holder if necessary.
Medicines Recall/Notification Classifications (Defect risk classification):
- National Patient Safety Alert(NatPSA), equivalent to Class 1 Medicines Recall– Defect presents a risk of death or disability. These are issued via the Central Alerting System (CAS) as NatPSA.
Class 1 medicines recall (Action Now , including out of hours) and includes Patient, Pharmacy and Wholesale Level Recall.
- Class 2 Medicines Recall – Defect may cause mistreatment/ harm to patient, however is not life-threatening /serious.
Class 2 medicines recall (Action within 48 hours) and includes Pharmacy and Wholesale Level Recall
Note that a NatPSA may be issued for any type of defect that presents a risk of death or disability.
- Class 3 Medicines Recall – Defect is unlikely to cause harm to patient and is carried out for other reasons such as, noncompliance with the marketing authorisation or specification.
Class 3 medicines recall (Action within 5 days) and includes Pharmacy and Wholesale Level Recall.
Note that a NatPSA may be issued for any type of defect that presents a risk of death or disability.
- Class 4 Medicines Notification – The MHRA also issues “Caution in Use” notices, where there is no threat to patients or no serious defect likely to impair product use or efficacy. Generally used for minor defects in packaging or other printed materials. “Caution in Use” notices may be issued where a defect has been identified however due to supply concerns product is unable to be recalled, alert will be used to provide advice to healthcare professionals in these instances.
Class 4 medicines recall (caution in use) and is distributed to Pharmacy and Wholesale Level.
Note that a NatPSA may be issued for any type of defect that presents a risk of death or disability.
- Company-led Medicines Recall/Notification – These are issued where the Licence Holder is able to identify the affected customers, therefore it is not necessary to issue an alert to the entire NHS/healthcare system, as the issue is only relevant to a small number of recipients.
The MHRA expectation for product quality related complaints, investigations and recalls requires Manufacturer’s Authorisation/ licence holder (MAH) to comply with the Human Medicines Regulations 2012 [SI 2012/1916] and the principles and guidelines for good manufacturing practice as detailed in the Good Manufacturing Practice Directive 2003/94/EC. (Regulations 37 to 41 of the Human Medicines Regulation 2012 [SI 2012/1916]), supported by Chapter 8 of the EU Good Manufacturing Practice Guidelines. A statutory duty is placed on the MAH to inform licensing authority without delay upon becoming aware of any defect which may lead to a product recall.
In regard to the wholesale distribution of medicinal products, the MAH must comply with the guidelines on good distribution practice in the case of a MAH in Great Britain, published under or apply by virtue of regulation C17, or in the case of a MAH in Northern Ireland, published by the European Commission in accordance with Article 84 of the 2001 Directive, as if the MAH were the holder of a Wholesale Dealer’s Authorisation (WDA)/ licence (Regulation 39(8) of the Human Medicines Regulation 2012 [SI 2012/1916]). Guidelines support the medicinal product recall process.
Where medicinal product is manufactured in a country other than the UK the applicant for the product MA should receive confirmation of responsibility from the non-UK manufacturer that a system has been implemented for recording and reviewing medicinal product complaints related to the MA with an effective system for prompt recall of the medicinal products at any time in the distribution network and the non-UK manufacturer must immediately inform the relevant licensing authority of any defect which could result in a recall from sale, supply or export or an abnormal restriction on such sale, supply or export.
Manufacturers who notify the Licensing Authority after a recall has already commenced will be in breach of the regulations. If it is not always clear whether a recall will be necessary manufacturers should always contact the DMRC for advice.
Manufacturer reporting of a medicinal product defect to the MHRA, the MAH can make use of the online Defect Reporting Form. The following information will be initially required by the DMRC as a minimum:
- Dates of manufacture and release of the affected product batch(es) to the market.
- An impact assessment quantifying the number of batches affected.
- Where admixture has occurred, dates of manufacture and release of the admixed product, closest to the complaint batch.
- Batch sizes, and pack size.
- Date of first and last distribution to the market.
- Review of complaint records for reports of similar defects.
- Estimation of stock under the Licence Holder’s control.
- Has the same batch been distributed to other countries?
Depending on the reported defects nature, the MAH may be required to quarantine remaining related stock whilst investigation is carried out. In possibly serious cases quarantine may extend to the wholesale distribution chain. If further investigation is required after the initial review the following may be needed:
- risk assessment including a clinical assessment, if appropriate, by the MAH
- review of all associated batch manufacturing, packaging, testing, release and distribution records for discrepancies which may provide insight on the suspected defect
- Examination and retesting of retained samples, if appropriate
- Details of any actions required by MAH to correct the defect in the future.
Timescales vary considerably depending on defect nature, consequent risk to public health, and possible complexity of the investigation. If there are concerns raised by the DMRC, specific deadlines may be imposed. Where problems are encountered in meeting these deadlines, these should be addressed by the MAH with the DMRC. Risk-based inspection (RBI) process will then consolidate information relating to the reported defect. The Inspector may wish to examine MAH’s records and investigation regarding the defect at an inspection.
The links below may provide guidance and information that may assist in the understanding and undertakings related to defective medicinal products and recall management:
- https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1007537/DMRC_Guide-to-Defective-Medicinal_Products-Aug2021.pdf
- https://www.gov.uk/drug-device-alerts
- https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
- https://www.legislation.gov.uk/uksi/2012/1916/contents/made