Effect of the new Annex 13 on Complaints and Recalls

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

As previously reported the final "Detailed Commission guidelines on GMP for IMPs for human use" have been published in December 2017 in Annex 13 of the EU GMP-Guidelines.

The sections 10 and 11 of the Detailed Commission Guideline cover the topics Complaints and Recalls. What has changed in comparison to the previous Annex 13 (Manufacture of Investigational Medicinal Products, IMPs)?

Pertaining to Complaints and Recalls the Detailed Commission Guideline contains references to:
• EU-GMP-Guidelines, Part 1, Chapter 8 (Complaints and Product Recall),
• Delegated Regulation (EU) 2017/1569,
• EU GCP Regulation 536/2014 (Clinical Trials Regulation, CTR).

Overall, there seems to be some lack of clarity between sponsor /manufacturer responsibility. For example, some of the activities are usually under the sponsor´s responsibility (e.g. according to Part 1, Chapter 8 of the EU GMP-Guidelines) but have now been placed under the manufacturer´s responsibility (e.g emergency unblinding, destruction) or have been deleted or moved from GMP to GCP.

A more detailed comparison concerning the changes in the guidelines in regard to complaints and recalls can be found below:

Section 10. COMPLAINTS of the Detailed Commission Guideline  
The following specific requirements have been added:

• "written procedures describing the actions to be taken upon receipt of a complaint at the manufacturing, storage or importation site."
• "All complaints should be documented and assessed to establish if they represent a potential quality defect or other issue."
• "The procedures should ensure that the sponsor is able to assess the complaints to determine if they justify the reporting of a serious breach, as required by Article 52 of Regulation (EU) No 536/2014" (Clinical Trials Regulation, CTR).

Article 52 "Reporting of serious breaches" of the CTR states: "1.The sponsor shall notify the Member States concerned about a serious breach of this Regulation or of the version of the protocol applicable at the time of the breach through the EU portal without undue delay but not later than seven days of becoming aware of that breach. 2. For the purposes of this Article, a ‘serious breach’ means a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial."

• "The investigation of quality defects should be performed in accordance with the principles detailed in the EU GMP Guidelines, Part I, Chapter 8 (Complaints and Product Recall)".

The following section is compromised in the previous Annex 13 and has been slightly amended in the Detailed Commission Guideline:

• "The conclusions of the investigation should be discussed between the manufacturer and the sponsor, if different, in a timely manner" (the previous Annex 13 also includes the importer). "This should involve the Qualified Person (QP) and those responsible for the relevant clinical trial in order to asses any potential impact on the trial, product development and on subjects."

Section 11. RECALLS AND RETURNS of the Detailed Commission Guideline 
11.1. Recalls

• "Procedures for retrieving investigational medicinal products and documenting this retrieval should in line with Article 14 of the Delegated Regulation be agreed by the sponsor in cooperation with the manufacturer, where different" (the previous Annex 13 also includes the importer).

Article 14 "Complaints, product recall and emergency unblinding" of the Delegated Regulation states:

1. The manufacturer shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints together with an effective system for recalling investigational medicinal products which have already entered the distribution network promptly and at any time. The manufacturer shall record and investigate any complaint concerning a defect and shall inform the sponsor and the competent authority of the Member States concerned of any defect that could result in a recall or abnormal restriction on supply. All trial sites shall be identified and, in so far as possible, the countries of destination shall be indicated. In the case of an authorised investigational medicinal product, the manufacturer shall, in cooperation with the sponsor, inform the marketing authorisation holder of any defect that could be related to that product.

2. Where blinding of investigational medicinal products is required by the protocol of a clinical trial, the manufacturer in conjunction with the sponsor shall implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall as referred to in paragraph 1. The manufacturer shall ensure that the procedure discloses the identity of the blinded product only in so far as it is necessary.

However, the EU GMP Guidelines, Part I, Chapter 8 (Complaints and Product Recall) states: "The sponsor should implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall. The sponsor should ensure that the procedure discloses the identity of the blinded product only in so far as is necessary."

• "The manufacturer, investigator and the sponsor's representative need to understand their obligations under the retrieval procedure" (previously: "The investigator and monitor need to understand their obligations under the retrieval procedure").
• "The procedures for retrieval of investigational medicinal products should be in accordance with the principles detailed in EU GMP Guidelines, Part I, Chapter 8".
• "To facilitate recall, a detailed inventory of the shipments made by the manufacturer should be maintained."

The following sentence of the previous Annex 13 has been deleted in the Detailed Commission Guideline:

• "The Sponsor should ensure that the supplier of any comparator or other medication to be used in a clinical trial has a system for communicating to the Sponsor the need to recall any product supplied."

As defined in the CTR "IMP" means a medicinal product which is being tested or used as a reference (comparator), including as a placebo, in a clinical trial. Therefore, the comparator is included in the above mentioned requirements for the IMP.

11.2. Returns

• As it is also written in the previous Annex 13: "Returned investigational medicinal products (IMPs) should be clearly identified and stored in an appropriately controlled, dedicated area. Inventory records of returned products should be kept."

The following sentence of the previous Annex 13 has been deleted in the Detailed Commission Guideline:

• "IMPs should be returned on agreed conditions defined by the sponsor, specified in approved written procedures."

This requirement has been moved from GMP to GCP, now presented in Article 51 (Traceability, storage, return and destruction of investigational medicinal products) of the CTR: 1. "IMPs shall be traceable. They shall be stored, returned and/or destroyed as appropriate and proportionate to ensure the safety of the subject and the reliability and robustness of the data generated in the clinical trial, in particular, taking into account whether the IMP is an authorised IMP, and whether the clinical trial is a low-intervention clinical trial. The first subparagraph shall also apply to unauthorised auxiliary medicinal products" (according to the CTR auxiliary medicinal products are medicinal products used in the context of a clinical trial but not as IMPs, such as medicinal products used for background treatment). 2."The relevant information regarding the traceability, storage, return and destruction of medicinal products referred to in paragraph 1 shall be contained in the application dossier."

11.3 Destruction

• "The manufacturer or sponsor’s representative should destroy IMPs only with prior written authorisation by the sponsor. The arrangements for destruction of IMPs have to be described in the protocol. Any arrangement between sponsor and manufacturer in this regard should be defined in their technical agreement."
• "Records of destruction operations should be retained, including a dated certificate of destruction or a receipt for destruction to the sponsor."

According to the previous Annex 13 the sponsor is responsible for the destruction of unused and/or returned IMPs and records should be kept by the sponsor:

•  "The Sponsor is responsible for the destruction of unused and/or returned investigational medicinal products. Investigational medicinal products should therefore not be destroyed without prior written authorisation by the Sponsor."
• "The records should be kept by the Sponsor".

The CTR and the Detailed Commission Guideline are expected to become applicable in the second half of 2019. More information on Annex 13 and the Detailed Commission Guideline can be found in EudraLex, Volume 4.