Guidance on the handling of quality defects in medicinal products

To ensure quality, safety and efficacy of marketed medicinal products,   there are strict requirements for the manufacture and distribution of medicinal products. Nevertheless, incidents may occur that affect the quality and safety of medicinal products and may pose a risk to public health. Where a quality defect is suspected or confirmed, it may be necessary to recall a product from the distribution chain in order to rapidly stop further sale and use.

NOMA’s role

The Norwegian Medical Products Agency (NOMA) supports relevant parties in the distribution chain in understanding the applicable regulatory framework and provides advice on risk classification and relevant market actions.

Upon receipt of a quality defect report, NOMA assesses all submitted documentation. In cooperation with the parties, we assess whether the quality defect may pose a risk to public health and whether a recall may lead to a shortage of medicinal products or supply difficulties. Sometimes the benefit of the medicinal products must be weighed against the risk of using the product, and in some cases it may be relevant to accept distribution  of medicinal products with a quality defect.

NOMA has the authority to overrule parties proposed decisions and may issue a decision of recall from the market if deemed  necessary.

NOMA assists with public notification through the media if the quality defect is assessed as serious  and requires recall from the end user/patient.

NOMA collaborates with European and international authorities in sharing notifications about quality defects through the Rapid Alert Network. The cooperation also includes notifications of suspected falsified medicinal products. NOMA is responsible for informing other EU/EEA countries of serious quality defects or falsifications discovered in Norway.

Who must report quality defects to NOMA

Manufacturers, wholesalers and marketing authorisation holders (MAHs) must inform the Norwegian Medical Products Agency (NOMA) of confirmed or suspected quality defects:

• that may pose a risk or disadvantage to the end user of a medicinal product intended for the Norwegian market, or
• that may affect the supply  of product in Norway.

Norwegian manufacturers who identify a quality defect in one of their medicinal products (including APIs and intermediates) must inform NOMA, regardless of whether the product is intended for the Norwegian or foreign market.

What must be reported to NOMA

Quality defects in medicinal products:

• Cases where it has been established that the quality of a medicinal product for human or veterinary use released for sale is not in accordance with the marketing authorisation (MA).
• Cases where a medicinal product supplied with special permit, named patient in Norway, does not have the expected quality, including failure to meet the manufacturer’s specifications.
• Quality defects arising during the manufacture of multidose and single-dose preparations.
• Quality defects arising during pharmacy compounding of medicinal products.

Quality defects in the distribution chain:

• Theft of medicinal products from a pharmacy, wholesaler, MAH or manufacturer, including theft during transport.
• Deviations arising in activities covered by the wholesale or manufacturing authorisation. This includes deviations during transport that may lead to, or have led to, breach of supply obligations, recall or shortages of medicinal products.
• Significant loss and wastage of narcotic drugs, for example due to theft, breakage, fire damage, water damage, etc., must be reported immediately to NOMA in accordance to Norwegian law.

Recall of medicinal products

A recall of medicinal products in Norway must be reported to NOMA.
Norwegian manufacturers who initiate a recall must report this to NOMA regardless of whether the product was produced for the Norwegian or foreign market.
NOMA should preferably receive the information in advance of the recall, or at the latest at the same time as information is sent to the relevant levels of the distribution  chain.

Other reportable events not defined as quality defects

If the quality defect for a medicinal product with a Norwegian MA is discovered before the product has been released for sale by the Qualified Person (QP), it is possible,  to apply to NOMA for batch-specific exemptions. This applies only in cases where approval for one batch or a limited number of batches is necessary in order to supply the medicinal product to the market and avoid shortages of medicinal products. Handling is described under Batch-specific exemptions – Norwegian Medical Products Agency.

Reporting of suspected or confirmed falsifications of medicinal products on the Norwegian market, or manufactured by a Norwegian producer for other markets, should be handled as described under Reporting of suspected falsified medicine – Norwegian Medical Products Agency.

Reporting of adverse reactions to medicinal products is handled as described under Adverse reaction reporting and the Adverse Reaction Register – Norwegian Medical Products Agency.

How to report a quality defect

Reporting form for quality defects

MAHs and manufacturers must report quality defects to NOMA using standardised reporting forms:

• Centrally authorised medicinal products: Use the EMA reporting form and send  to both the EMA and NOMA. For more information on reporting and the form, see Quality defects and recalls | European Medicines Agency (EMA).
• Other medicinal products and quality defects in the distribution chain: Use NOMA’s reporting form: Notification of quality defect (in Norwegian only).

The completed form must be sent to NOMA by email to rapidalert@noma.no.

Quality defects related to pharmacy-prepared medicinal products must be reported to NOMA as described under Guidance regarding deviations in pharmacy compounding – Norwegian Medical Products Agency.

To assess a quality defect and the proposed actions, the report must include the following:

• Description of the quality defect and the investigations carried out, including results.
• Assessment of patient risk (Health Hazard Assessment).
• Root Cause Analysis.
• Description of corrective and preventive actions (CAPA). If an action plan has been established, it must include deadlines for implementation.
• Statement of the desired market actions. If no market actions are considered necessary, this must be justified. If recall is considered an appropriate market action, the level of the recall must be stated.

Much of the information will be included in the reporting form; other documents may be submitted as separate attachments. Documentation may be preliminary if not all information is available at the time of reporting. Documentation must be submitted as soon as it becomes available, and no later than within 30 days.

NOMA will close the case when a final report has been received and all measures have been implemented.

Product complaints

Patients, doctors, veterinarians or other healthcare professionals who suspect a quality defect or fault in a medicinal product must submit a complaint about the product by:

1. contacting the pharmacy or shop where the medicinal product was purchased. They will forward the complaint to the MAH or supplier directly or via their wholesaler.
2. alternatively, contacting the MAH or its representative directly. Contact details are provided in the medicinal product’s package leaflet.

To ensure a thorough investigation, the following information must be available: product name, pack size, strength and batch/lot number.

Manufacturers or MAHs will often request both photographs and the original packaging in order to carry out thorough investigations.

The reporter must receive feedback on the outcome of the investigations.

NOMA may be contacted for assistance if contact with the MAH, its representative or supplier cannot be established, or if feedback is not provided.

NOMA does not handle complaints about medicinal products from the public or healthcare services.

All parties of the distribution chain that sell medicinal products must keep records of complaints received about medicinal products they have sold.

Contact information

E-mail: rapidalert@noma.no. 

If there is a need to make a phone call during NOMA's opening hours, please use the direct number +47 922 85 268 or the switchboard number +47 22 89 77 00, which will transfer the call to the duty case officer. Information must also be submitted in writing when contact is made by phone.

If there is a need to report serious quality defect cases that are urgent outside NOMA’s opening hours, the Director-General of NOMA may be contacted by phone at +47 909 49 257.

Actions following a quality defect

Manufacturers, wholesalers and MAHs are responsible for implementing actions in the event of suspected or confirmed quality defects. Corrective and preventive actions must be based on investigation of root cause and assessment of patient risk.

The need for market actions must be assessed on the basis of the severity of the quality defect, patient risk and the risk of shortages of medicinal products.

The most common market actions include recall of the product, preparation of a “Direct Healthcare Professional Communication” (DHPC), or publication of a news article on dmp.no.

Recall

A medicinal product may be recalled at three different levels:

• Wholesaler level (only from the wholesaler)
• Pharmacy level (from wholesaler and pharmacy, and in some cases also hospital wards)
• Patient level (from wholesaler, pharmacy, hospital wards, nursing homes and patients)

The recall level is assessed based on the classification of the quality defect and patient risk.

Table 1. Indicative classification of quality defects and recall level

Table displaying indicative classification of quality defects and recall level

Classification	Risk to patient	Recall level	Deadline for notification to be received by all relevant distribution levels
Class 1	Potentially life-threatening, or may pose a serious health risk	Patient level	Immediately – without delay
Class 2	May cause illness/injury or incorrect treatment	Pharmacy level or Patient level	24 hours
Klasse 3	Unlikely to cause any harmful effects	Wholesaler level or Pharmacy level or No recall necessary	2 working days

 

The manufacturer, wholesaler and MAH are responsible for informing all their customers if one or more batches of a medicinal product are recalled due to a quality defect. They must ensure that the recall is received by the necessary levels of the distribution chain, including customers in third countries.

A recall notification must be drafted in a manner that allows the recipient to forward it in its entirety to their customers, if necessary, to prevent delays. The notification must be clearly labelled “Recall” and must at a minimum contain the following information:

1. Information about the notifier

Name of company, address and contact details; email and telephone number

2. Product information

Nordic article number, name of the medicinal product, active substance and strength, pharmaceutical form, pack size and batch number

3. Reason for recall, scope and desired handling of the product

• Description of the defect/reason for recall
• Consequences/hazards/assessment of risk to patients
• Scope: number of packs confirmed/suspected to be affected/supplied/distributed
• Classification and recall level (see Table 1 for guidance)
• Desired handling of recalled product: local destruction or return to wholesaler/MAH
• Information on consequences and handling related to the FMD, if relevant

When a company receives a recall notification, the products must be immediately placed in quarantine and handled as described in the notification. Further, customers must be informed at the level specified in the recall and within the deadlines given in Table 1.

Recall from pharmacies in Norway are managed by the wholesaler that distributed the product in Norway. If more than one pharmacy wholesaler has distributed the product, distribution of the recall is coordinated by one of the pharmacy wholesalers in accordance with the applicable agreement.

Companies that sell medicinal products to retail stores, or that themselves distribute medicinal products directly to pharmacies without using the three major pharmacy wholesalers, must have their own system for notification and recall.

Follow-up of a recall

 A final report must be submitted to DMP following a recall. 
The final report must be sent to NOMA no later than 30 days after the recall was initiated, and should at a minimum include the following:

• Brief summary of the sequence of events and the recall.
• Brief description of the investigations carried out, and the results.
• Results from the Root Cause Analysis.
• Description of corrective and preventive actions (CAPA) implemented or planned, including implementation deadlines.
• Product accounting for the recalled batch, preferably in tabular format. The accounting must clearly show how many units were impacted by the recall and the distribution of these (stock held at own warehouse, 3PL warehouse, stock held by Norwegian wholesalers and pharmacies (if known)). In addition, it must show the number of units returned and destructed from the respective pharmacies and wholesalers/warehouses.
• Copy of destruction certificates for destructed units.
• Confirmation that the batch has been decommissioned from the EMVS database.

The points above may also be included in a complete deviation report or investigation report/final investigation report.

Direct Healthcare Professional Communication (DHPC)

DHPC is an information letter addressed directly to healthcare professionals. The letter is prepared by the MAH in cooperation with national authorities and, where relevant, the EMA. A DHPC must be distributed in accordance with the deadlines set out in the communication plan.

Letters sent to Norwegian healthcare professionals must be translated into Norwegian. Use the template for DHPC (in Norwegian only) in cases of quality defects and send to rapidalert@dmp.no. Attach the original English version (where relevant) and the communication plan with deadlines.

NOMA comments on the content and the Norwegian translation but does not approve the letters.

The final version of the DHPC must be distributed to healthcare professionals in PDF format by the MAH as described under Guidance for submission of Norwegian translations of direct healthcare professional communication (DHPC).

NOMA publishes the DHPCs on its website when appropriate. See list of published DHCP letters (in Norwegian only).

News article

A news article may be used to reach affected end users and groups of healthcare professionals, often in connection with a patient level recall.

The text is prepared by NOMA in cooperation with the MAH and published on the Norwegian version of this webpage. 

Both news articles and DHPCs may, where appropriate, be linked to alerts in FEST. The information will be visible in doctors’ medical record systems and in the Norwegian Medicines Compendium (Felleskatalogen).

General requirements for wholesalers, manufacturers and MAHs

Procedure for handling quality defects and recall

The company must have a written procedure for registering and processing received notifications of suspected or confirmed quality defects in medicinal products, including recall procedures.

Notifications must be handled by a designated person appointed by management. The responsibility should be set out in a job description, and the person should have a permanent deputy so that there is always (24/7) someone available to handle notifications of quality defects.

Notifications of quality defects must be forwarded to the MAH, manufacturer or supplier so that investigations can be initiated.

If the investigations show that there is a quality defect, NOMA must be informed. If contact with the MAH or supplier cannot be established, or if feedback is not provided, NOMA may be contacted for assistance. This applies regardless of whether the medicinal product has a marketing authorisation in Norway.

Testing the recall procedure (mock recall)

NOMA expects the effectiveness of internal recall procedures to be verified annually.

As a minimum, the test should include the following:

• Review of the internal procedure/SOP
• Review of NOMA’s guidance on handling quality defects in medicinal products
• Check that internal communication procedures deliver the required response
• Check that contact details for external partners are up to date and functional
  • NOMA contact details can be checked by ensuring that internal procedures are updated with the current contact details from NOMA’s website
  • NOMA should not be contacted for verification
• Check that, in a hypothetical recall scenario, all affected products and/or batches can be traced

A final report must be prepared following the exercise. The report should at a minimum include:

• A conclusion
• Description of necessary changes or proposals for improvement

The report must be archived by the company and must be available for presentation during inspection by NOMA.