Commission Implementing Regulation (EU) 2025/2154 of 17 October 2025 laying down good manufacturing practice for active substances used as starting materials in veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council

THE EUROPEAN COMMISSION,

Having regard to the Treaty on the Functioning of the European Union,

Having regard to Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC (1), and in particular Article 93(2) thereof,

Whereas:

(1) In accordance with Regulation (EU) 2019/6, veterinary medicinal products manufactured in the Union, including veterinary medicinal products intended for export as well as veterinary medicinal products imported into the Union, are to be manufactured in accordance with good manufacturing practice and contain as starting materials only active substances which have been manufactured in accordance with good manufacturing practice for active substances.

(2) The Commission is to adopt good manufacturing practice for active substances used as starting materials in veterinary medicinal products (the ‘active substances’) applicable in the Union. The good manufacturing practices applicable in the Union should continue to be aligned with relevant international standards.

(3) Compliance with the requirements for good manufacturing practice for active substances applicable in the Union should be ensured by manufacturers of active substances (‘manufacturers’). To avoid placing any restraint upon the development of any new concepts or new technologies, manufacturers of active substances should be allowed to implement alternative approaches to those set out in this Regulation only if they are able to demonstrate that the alternative approach is capable of meeting the same objectives and that the quality and purity of the active substances is ensured.

(4) The manufacture of sterile active substances presents specific risks that should be addressed with a view to ensure the quality of such active substances. To this end, the sterilisation and aseptic processing of sterile active substances should be performed in accordance with the requirements set out in Annex I to Commission Implementing Regulation (EU) 2025/2091 (2) on good manufacturing practice for veterinary medicinal products.

(5) The manufacture of active substances from biological origin present specific characteristics that should be addressed with a view to ensure the quality of such active substances. To this end, requirements set out in Annex II to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products should be applied as relevant.

(6) The manufacture of active substances from herbal origin present specific characteristics that should be addressed with a view to ensure the quality of such active substances. To this end, requirements set out in Annex III to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products should be applied as relevant.

(7) Active substances used in parasiticidal veterinary medicinal products for the target species bees and active substances used in ectoparasiticidal veterinary medicinal products for external application are often produced for use in other types of products and the quantity needed for the production of veterinary medicinal products is too small to be economically viable. In order to ensure availability of parasiticidal veterinary medicinal products for bees and ectoparasiticidal veterinary medicinal products, this Regulation should not apply to the production of those active substances. However, the manufacturing process thereof should be adequate to ensure the quality and purity of the active substances. Additionally, the specifications provided for by the manufacturer of the veterinary medicinal product should be complied with.

(8) Where there is a continuous process from the sourcing or isolation of an active substance from a biological source to the manufacturing of the finished product, such as in the case of veterinary medicinal products that consist of cells, viral-based vaccines or phages, the entire manufacturing process is subject to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products and this Regulation should therefore not apply to them.

(9) Where there is a continuous process from the manufacture of the active substance gas to the manufacturing of the finished product, the entire manufacturing process is subject to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products and this Regulation should therefore not apply to them.

(10) Manufacturers should ensure the identity, integrity, traceability and consistent quality of the active substances during their production. To achieve this objective, manufacturers should implement a comprehensive quality management system.

(11) Through product quality reviews, manufacturers should verify the consistency of the existing processes, the appropriateness of current specifications, detect trends, and identify product and process improvements. Where appropriate, the outcome of such reviews should lead to the implementation of corrective or preventive measures.

(12) In order to ensure that the active substances meet the required quality standards and comply with the terms of the marketing authorisation and with good manufacturing practice, manufacturers should perform regular self-inspections.

(13) In order to ensure the quality of the active substances, manufacturers should have an adequate number of competent personnel with clear responsibilities. Initial and on-going training relevant to the assigned tasks should be provided to the personnel.

(14) Appropriate hygiene standards should be maintained at all times during the manufacturing process.

(15) In order to ensure the quality of the active substances, manufacturers should have suitable premises and equipment for the manufacture and control of the active substances as well as suitable premises for the storage of materials and products. Such premises and equipment should be adequately maintained. Qualification and validation of the premises and equipment, including utilities and systems used during manufacture of active substances, should be set out as a basic requirement of good manufacturing practice.

(16) In order to ensure that the use of computerised systems does not increase the risks to the quality of the active substances, certain requirements for the use of such systems should be laid down.

(17) A comprehensive documentation system should be set out as a key component of the quality management system. The documentation system should ensure that appropriate instructions and specifications are laid down, including relevant controls and monitoring procedures, with a view to ensuring the quality of the active substances. Additionally, the documentation system should ensure that all the activities that, directly or indirectly, may affect the quality of the active substances are duly recorded and that the integrity of the data is maintained throughout the relevant retention period.

(18) Requirements concerning the handling of materials and products, the qualification of suppliers, the prevention of cross-contamination and packaging operations should be set out.

(19) Production and in-process controls should be performed in order to assure the quality of the active substance and intermediates thereof.

(20) Laboratory control procedures should be implemented to ensure that materials are not released for use and products are not released for supply until their quality has been verified. As such, laboratory control should encompass sampling, specifications and testing, as well as organisational measures, documentation and release procedures.

(21) Correct sampling is essential to ensure the quality of the manufactured products. Reference samples should be kept as a record of the batch of active substance and for assessment in the case of quality investigations.

(22) In order to ensure that quality problems are swiftly identified and addressed, a system to record and investigate suspected quality defects and quality-related complaints should be put in place by manufacturers. In addition, procedures should be established to deal with recalls.

(23) In order to ensure that the outsourcing of activities related to the manufacture and control of active substances does not increase the risks to the quality of the active substances, certain requirements should be laid down. In particular, the outsourcing should be done in writing and there should be a clear delineation of the responsibilities of each party.

(24) The manufacture of certain types of active substances warrants specific consideration. Additional requirements should be implemented in the manufacture of active substances or intermediates thereof manufactured by cell culture or fermentation and in the manufacture of active substances gases. It is therefore necessary to set out certain adjustments to the good manufacturing practice requirements or, where appropriate, additional requirements for those products.

(25) While the good manufacturing practice requirements set out in this Regulation remain aligned with applicable requirements under Directive 2001/82/EC of the European Parliament and of the Council (3), time should be given to competent authorities and concerned stakeholders to become acquainted with the provisions of this Regulation. Accordingly, the application thereof should be deferred.

(26) The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Veterinary Medicinal Products,

HAS ADOPTED THIS REGULATION:

CHAPTER I

GENERAL PROVISIONS

Article 1

Subject matter and scope

(a) active substances to be used in parasiticidal veterinary medicinal products for the target species bees;

(b) active substances to be used in ectoparasiticidal veterinary medicinal products for external application to animals;

(c) biological active substances where there is a continuous process from the sourcing or isolation of the active substance from a biological source to the manufacture of the finished product;

(d) gases where there is a continuous manufacturing and no intermediate storage of gas between the manufacture of the active substance and the manufacture of the veterinary medicinal product is possible.

Article 2

Definitions

For the purposes of this Regulation, the following definitions shall apply:

(1) ‘signed’ means the record of the individual who performed a particular action or review. This record can be initials, a full handwritten signature, a personal seal, or an advanced electronic signature as defined in Article 3(11) of Regulation (EU) No 910/2014 of the European Parliament and of the Council (4);

(2) ‘quality risk management’ means a systematic process, applied both proactively and retrospectively, for the assessment, control, communication and review of risks to the quality of the active substance;

(3) ‘intermediate’ means a material produced during steps of the processing of an active substance that undergoes further molecular change or purification before it becomes an active substance;

(4) ‘qualification’ means the process of demonstrating that entities, premises, equipment, utilities, systems or materials are suitable for the intended task and can deliver the expected outcomes;

(5) ‘in-process controls’ means the checks performed during production in order to monitor and, if necessary, adjust the process to ensure that the intermediate or active substance conforms to the required specifications;

(6) ‘validation’ means the process of demonstrating that a method or process is suitable for its intended use;

(7) ‘batch’ means a defined quantity of materials or product that undergo the same process(es) so that it can be expected to be homogeneous. In the case of continuous manufacturing, a batch corresponds to a defined fraction of the production, characterised by its intended homogeneity;

(8) ‘raw material’ means starting materials, reagents, and solvents intended for use in the production of intermediates or active substances;

(9) ‘area’ means a space. A specific set of rooms within a building associated with the manufacture of one or more products that has a common air handling unit is considered as a single area;

(10) ‘cross-contamination’ means the contamination of a material or product with another material or product;

(11) ‘quarantine’ means the isolation -physically or by other effective means- of materials, intermediate or active substances whilst awaiting a decision on their release or refusal;

(12) ‘reprocessing’ means introducing an intermediate or active substance, including one that does not conform to standards or specifications, back into the manufacturing process and repeating a crystallisation step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process; excluding continuation of a process step after an in-process control test has shown that the step is incomplete;

(13) ‘campaign manufacture’ means the manufacture of a series of batches of the same product in sequence in a given period of time followed by strict adherence to preestablished control measures before transfer to another product. Use of the same equipment for distinct products is possible in campaign manufacture provided that appropriate control measures are applied;

(14) ‘bulk’ means any product which has completed all processing stages up to, but not including, final packaging;

(15) ‘blending’ means the process of combining materials complying with the same specification to produce a homogeneous intermediate or active substance;

(16) ‘primary reference standard’ means a substance that has been shown by an extensive set of analytical tests to be authentic material of high purity and that is obtained from an officially recognised source, or prepared by independent synthesis, or obtained from existing production material of high purity, or prepared by further purification of existing production material;

(17) ‘secondary reference standard’ means a substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis;

(18) ‘reference sample’ means a sample of a batch of materials used in the manufacture of the active substances used as starting materials in veterinary medicinal products which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned;

(19) ‘reworking’ means subjecting an intermediate or active substance that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or active substance;

(20) ‘mother liquor’ means the residual liquid which remains after the crystallisation or isolation processes;

(21) ‘classical fermentation’ refers to processes that use microorganisms existing in nature or modified by conventional methods such as irradiation or chemical mutagenesis, to produce active substances used as starting materials.

Article 3

Starting point for the manufacture of active substances

CHAPTER II

QUALITY MANAGEMENT SYSTEM

Article 4

Implementation of a quality management system