Subject matter and scope
1. This Regulation lays down the requirements for good manufacturing practice for veterinary medicinal products.
2. The manufacture of sterile veterinary medicinal products and aseptic manufacturing shall comply with the additional requirements set out in Annex I.
3. The manufacture of biological and immunological veterinary medicinal products shall comply with the additional requirements set out in Annex II. However, this Regulation shall not apply to inactivated immunological veterinary medicinal products which are manufactured from pathogens and antigens obtained from an animal or animals in an epidemiological unit and used for the treatment of that animal or those animals in the same epidemiological unit or for the treatment of an animal or animals in a unit having a confirmed epidemiological link.
4. Additional requirements and specific adaptations to the requirements laid down in this Regulation are set out in Annex III for the following veterinary medicinal products:
(a)
herbal veterinary medicinal products;
(b)
veterinary medicinal products intended for incorporation into medicated feeding stuffs;
(c)
ectoparasitic veterinary medicinal products for external application;
(d)
liquids creams and ointments;
(e)
medicinal gases;
(f)
pressurised metered dose aerosol products for inhalation.
5. Whilst meeting the requirements laid down in this Regulation demonstrates compliance with good manufacturing practice for veterinary medicinal products, alternative approaches to the requirements provided for in this Regulation may be implemented where it is duly justified that the alternative approach is capable of meeting the same objectives and that the quality, safety and efficacy of the veterinary medicinal product concerned and compliance with the terms of the marketing authorisation is ensured.
Definitions
For the purposes of this Regulation, the following definitions shall apply:
(1)
‘pharmaceutical quality system’ means the total sum of the measures implemented as part of the manufacturing process to ensure that medicinal products are of the quality required for their intended use;
(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 veterinary medicinal product across the product’s lifecycle;
(3)
‘manufacturing site’ means a site that is engaged in any of the activities for which a manufacturing authorisation is required in accordance with Article 88(1) of Regulation (EU) 2019/6;
(4)
‘batch’ means a defined quantity of materials or product that undergo the same process(es) so that it can be expected to be homogeneous. For the control of the finished product, a batch of a veterinary medicinal product comprises all the units of a pharmaceutical form which are made from the same initial mass of materials and have undergone a single series of manufacturing operations or a single sterilisation operation or, in the case of a continuous production process, all the units manufactured in a given period of time. In the case of continuous manufacturing, a batch corresponds to a defined fraction of the production, characterised by its intended homogeneity;
(5)
‘bulk product’ means any product which has completed all processing stages up to, but not including, final packaging;
(6)
‘intermediate product’ means a partly processed material which must undergo further manufacturing steps before it becomes a bulk product;
(7)
‘finished product’ means a veterinary medicinal product that has undergone all the stages of production, including packaging in its final container;
(8)
‘packaging’ means all operations, including filling (with the exception of sterile filling) and labelling, which a bulk product has to undergo in order to become a finished product;
(9)
‘packaging material’ means any material employed in the packaging of a veterinary medicinal product, excluding any outer packaging used for transportation or shipment. Packaging material can relate to immediate packaging or outer packaging;
(10)
‘in-process controls’ means the checks performed during production in order to monitor and, if necessary, adjust the process to ensure that the product conforms to the required specifications. Environmental monitoring and equipment controls are part of in-process controls;
(11)
‘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;
(12)
‘validation’ means the process of demonstrating that a method or process is suitable for its intended use;
(13)
‘reference sample’ means a sample of a batch of materials used in the manufacture of a veterinary medicinal product or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned;
(14)
‘retention sample’ means a sample of a fully packaged unit from a batch of finished product which is stored for identification purposes;
(15)
‘reprocessing’ means the treatment of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations;
(16)
‘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;
(17)
‘clean area’ means an area designed, maintained, and controlled to prevent particle and microbiological contamination;
(18)
‘contained area’ means an area that is designed (including air handling and filtration), maintained and controlled so as to prevent contamination of the external environment by biological or other agents;
(19)
‘segregated area’ means an area within a manufacturing site that has separate storage, separate production suite with separate HVAC (heat, ventilation and air conditioning), dedicated equipment reserved solely for the production of one type of product with a specific risk profile and restrictions on the movement of personnel and equipment;
(20)
‘airlock’ means an enclosed space with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude ingress of particle matter and microorganism contamination from a lesser controlled area. A pass-through hatch has the same meaning as ‘airlock’ but is typically of a smaller size;
(21)
‘closed system’ means a system designed and operated so as to avoid exposure of the product or material to the room environment. Materials may be introduced to a closed system, but the addition must be done in such a way so as to avoid exposure of the product to the room environment (e.g. by means of sterile connectors or fusion systems). A closed system may need to be opened (e.g. to install a filter or make a connection) but it is returned to a closed state through a sanitisation or sterilisation step prior to process use;
(22)
‘cross-contamination’ means the contamination of a material or a product with another material or product;
(23)
‘isolator’ means an enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (e.g. surrounding cleanroom air and personnel). There are two major types of isolators:
(a)
closed isolator systems, which exclude external contamination of the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations;
(b)
open isolator systems, which are designed to allow for the continuous or semi-continuous ingress or egress of materials during operations through one or more openings. Openings are engineered (e.g. using continuous overpressure) to exclude the entry of external contaminant into the isolator;
(24)
‘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;
(25)
‘aseptic processing/manufacturing’ means processing or manufacturing activities performed under conditions which prevent contamination;
(26)
‘quarantine’ means the isolation – physically or by other effective means – of materials, intermediate, bulk or finished products whilst awaiting a decision on their release or refusal;
(27)
‘reconciliation’ means a comparison, having due regard for normal variation, between the amount of product or materials theoretically and actually produced or used;
(28)
‘bracketing’ means an approach such that only the extremes of certain predetermined factors are tested or validated. The design assumes that validation of any intermediate levels is covered by the tests or validation of the extremes;
(29)
‘matrix’ means an approach where a subset of the total number of possible samples for all factor combinations is tested at a specified time point and another subset of samples is tested for all factor combinations at a subsequent time point. The results of each subset of samples is assumed to be representative for all samples at a given time point;
(30)
‘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 ( 3 ) .
Role of the marketing authorisation holder regarding good manufacturing practice
1. The marketing authorisation holder shall ensure that the specifications and instructions submitted to the manufacturer are in accordance with the terms of the marketing authorisation. Changes to the specifications or instructions required to comply with a variation to the terms of the marketing authorisation shall be notified immediately to the manufacturer.
2. The marketing authorisation holder shall communicate swiftly to the manufacturer any information that is relevant to the manufacturing process, as well as any relevant information that may have an impact on the quality, safety and efficacy of the veterinary medicinal product. In turn, the manufacturer shall inform the marketing authorisation holder of any information that is gathered in the context of the manufacturing activities and that is relevant for the quality, safety or efficacy of the veterinary medicinal product.
3. Where the marketing authorisation holder is a different entity than the manufacturer, he or she shall evaluate the results of the product quality review referred to in Article 6 and assess if any appropriate measure should be implemented.
4. The obligations of the marketing authorisation holder and the manufacturer and vis-à-vis each other shall be defined in writing.
