Subject matter and scope
1. This Regulation lays down the requirements for good manufacturing practice for active substances used as starting materials in veterinary medicinal products (‘active substances’).
2. This Regulation applies to the manufacture of sterile active substances only up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing shall be performed in accordance with the requirements set out in Annex I to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products.
3. The manufacture of biological active substances shall comply with the additional requirements set out in Annex II to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products, with the exception of active substances referred to in paragraph 7.
4. The manufacture of herbal active substances shall be subject to the additional requirements set out in Annex III to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products.
5. This Regulation, except its Chapter XVII, applies to manufacturers of active substances other than the substances referred to in paragraph 7 of this Article.
6. Chapter XVII applies to entities involved in the repackaging or relabelling of active substances other than the substances referred to in paragraph 7 of this Article.
7. This Regulation does not apply to the following active substances:
(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.
8. Chapter VII does not apply to the production of active substance gases performed by air separation.
9. Articles 48 and 49 do not apply to the production of active substance gases for which the initial stability studies have been replaced by bibliographic data.
10. Article 50 does not apply to the production of active substance gases, unless otherwise specified.
11. Whilst meeting the requirements laid down in this Regulation demonstrates compliance with good manufacturing practice, the manufacturer of active substances (the ‘manufacturer’) may implement alternative approaches to the requirements provided for in this Regulation where it is duly justified that the alternative approach is capable of meeting the same objectives and that the quality and purity of the active substance is ensured.
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.
Starting point for the manufacture of active substances
1. The starting point at which the manufacture of an active substance starts shall be determined in accordance with the Annex to this Regulation. The reasons for the implemented approach shall be documented.
2. From the point determined in accordance with paragraph 1, the requirements set out in this Regulation shall apply.
