Prováděcí nařízení Komise (EU) 2025/2091 ze dne 17. října 2025, kterým se stanoví správná výrobní praxe pro veterinární léčivé přípravky v souladu s nařízením Evropského parlamentu a Rady (EU) 2019/6

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/ECOJ L 4, 7.1.2019, p. 43 , ELI: http://data.europa.eu/eli/reg/2019/6/oj. , and in particular Article 93(2) thereof,

This Regulation lays down the requirements for good manufacturing practice for veterinary medicinal products.

The manufacture of sterile veterinary medicinal products and aseptic manufacturing shall comply with the additional requirements set out in Annex I.

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.

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.

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.

OJ L 4, 7.1.2019, p. 43 , ELI: http://data.europa.eu/eli/reg/2019/6/oj.

(1) In accordance with Regulation (EU) 2019/6, holders of a manufacturing authorisation (manufacturers) are required to comply with good manufacturing practice. Compliance with good manufacturing practice is required for the manufacture of veterinary medicinal products in the Union, including the manufacture of veterinary medicinal products intended for export, as well as for imports of veterinary medicinal products into the Union.

(2) The Commission is to adopt good manufacturing practice for veterinary medicinal products applicable in the Union. The good manufacturing practice for veterinary medicinal products applicable in the Union should continue to be aligned with relevant international standards.

(3) The manufacture of certain types of veterinary medicinal products warrants specific consideration. Additional requirements should be implemented in the manufacture of sterile veterinary medicinal products and for aseptic manufacturing. An end-product test for sterility is limited in its ability to detect contamination. In contrast, data derived from in-process controls and by monitoring relevant sterilisation parameters can provide more accurate and relevant information to support the sterility assurance of the product. Accordingly, sole reliance on end testing for the demonstration of sterility should not be possible.

(4) Additional requirements should also be implemented in the manufacture of biological and immunological veterinary medicinal products, including measures to protect workers and the environment, as well as specific quality and traceability requirements regarding the use of materials of biological origin. In cases 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 (e.g. veterinary medicinal products that consist of cells, viral-based vaccines or phages), the requirements of good manufacturing practice for active substances should not apply; instead the requirements laid down in this Regulation should apply to the entire manufacturing process. However, this Regulation should not apply to the manufacture of 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.

(5) The manufacture of herbal veterinary medicinal products, veterinary medicinal products intended for incorporation into medicated feedingstuffs, ectoparasitic veterinary medicinal products for external application, liquids creams and ointments, medicinal gases and pressurised metered dose aerosol veterinary medicinal products for inhalation warrants specific consideration. It is therefore necessary to set out certain adjustments to the good manufacturing practice requirements or, where appropriate, additional requirements for those products.

(6) The manufacture of homeopathic veterinary medicinal products subject to a registration procedure pursuant to Article 86(1) of Regulation (EU) 2019/6 is to comply with good manufacturing practice. The requirements set out in this Regulation should apply adapted to the fact that such products do not have a marketing authorisation. Accordingly, references to the terms of the marketing authorisation should, for these products, be understood as referring to the terms of the registration.

(7) In accordance with Regulation (EU) 2019/6, certificates of good manufacturing practice are to be issued when compliance with the requirements set out in this Regulation is demonstrated. To avoid placing any restraint upon the development of any new concepts or new technologies, manufacturers 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, safety and efficacy of the veterinary medicinal product as well as its compliance with the terms of the marketing authorisation is ensured.

(8) Good manufacturing practice should apply throughout the lifecycle of the veterinary medicinal product, including technology transfer and up to the discontinuation of production.

(9) For the manufacturer to be able to comply with good manufacturing practice, cooperation between the manufacturer and the marketing authorisation holder is necessary. Where the manufacturer and the marketing authorisation holder are different legal entities, the obligations of the manufacturer and marketing authorisation holder vis-à-vis each other should be specified in a technical agreement between them.

(10) Manufacturers should ensure that the products are fit for their intended use, comply with the requirements of the marketing authorisation and do not create risks for the treated animals or the user due to inadequate quality. To achieve this objective, manufacturers should implement a comprehensive pharmaceutical quality 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. Regular self-inspections should also be conducted to verify the effectiveness of the pharmaceutical quality system.

(12) In order to ensure the quality of veterinary medicinal products, 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.

(13) In order to ensure the quality of veterinary medicinal products, manufacturers should have suitable premises and equipment for the manufacture and control of the veterinary medicinal products 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 the manufacture of veterinary medicinal products, should be set out as a basic requirement of good manufacturing practice.

(14) In order to ensure the quality of veterinary medicinal products, manufacturers should ensure that appropriate hygiene standards are maintained at all times during the manufacturing process.

(15) A comprehensive documentation system should be set out as a key component of the pharmaceutical quality 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 veterinary medicinal products and compliance with the terms of the marketing authorisation. Additionally, the documentation system should ensure that all the activities that, directly or indirectly, may affect the quality of veterinary medicinal products are duly recorded and that the integrity of the data is maintained throughout the relevant retention period.

(16) Through process validation, the manufacturers should ensure that the critical aspects of the manufacturing process are duly controlled and that a consistent production is ensured in accordance with the quality requirements set out in the marketing authorisation.

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

(18) Quality 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, quality control should encompass sampling, specifications and testing, as well as organisational measures, documentation and release procedures.

(19) Correct sampling is essential to ensure the quality of veterinary medicinal products. Reference samples and retention samples should be kept as a record of the batch of finished product or of batches of materials used in the manufacture of the veterinary medicinal product and for assessment in the case of quality investigations.

(20) In order to ensure the quality of veterinary medicinal products and compliance with the terms of the marketing authorisation, manufacturers should perform batch release tests and in-process controls. An on-going stability programme should be implemented also.

(21) Real time testing and parametric release testing should be acceptable under certain conditions.

(22) Details on the process of certification by the qualified person and batch release should be laid down. In the case of veterinary medicinal products manufactured outside the Union, the certification process should be regarded as the final step in the manufacturing process which precedes the actual placing on the market.

(23) In order to ensure that the use of computerised systems does not increase the risks to the quality of veterinary medicinal products, certain requirements for the use of such systems should be laid down.

(24) In order to ensure that the outsourcing of activities related to the manufacture and control of veterinary medicinal products does not increase the risks to the quality of the product, 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.

(25) 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.

(26) Specific requirements for the use of ionising radiation in the manufacture of veterinary medicinal products should be laid down.

(27) 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 CouncilDirective 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products (OJ L 311, 28.11.2001, p. 1 , ELI: http://data.europa.eu/eli/dir/2001/82/oj). , 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.

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

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

Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products (OJ L 311, 28.11.2001, p. 1 , ELI: http://data.europa.eu/eli/dir/2001/82/oj).

Article 1 Article 1 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.

Article 2 Article 2 Definitions

Article 3 Article 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.

Article 4 Article 4 Implementation of a pharmaceutical quality system 1.Manufacturers shall have in place a comprehensive pharmaceutical quality system designed to ensure the quality of the veterinary medicinal products. 2.Compliance with good manufacturing practice and the terms of the marketing authorisation shall be an essential part of the pharmaceutical quality system.

Article 5 Article 5 Requirements of the pharmaceutical quality system 1.The design of the pharmaceutical quality system shall be based on the following risk management principles: (a) the evaluation of the risks to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the user and the safety of the animals treated;(b) the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk. 2.While some aspects may be company-wide, the pharmaceutical quality system shall be developed and implemented at site level. 3.The size of the company and complexity of the relevant activities shall be taken into consideration in developing a pharmaceutical quality system or modifying an existing one. Senior management shall have the ultimate responsibility to ensure the effectiveness of the pharmaceutical quality system and, to that end, shall ensure that appropriate resources are allocated. 4.The pharmaceutical quality system shall be duly documented and the effectiveness thereof shall be monitored. 5.The pharmaceutical quality system shall ensure that: (a) there is an adequate number of personnel with the necessary qualifications and adequate training and there is clear allocation of responsibilities, including managerial responsibilities;(b) the premises and equipment are suitable for the intended use and they are appropriately maintained;(c) there is an adequate documentation system that ensures that appropriate specifications are laid down for materials used in the manufacture of the veterinary medicinal product, intermediate product, bulk product and finished product, that the production and quality control procedures are clearly defined, and that appropriate records are kept;(d) arrangements are put in place for the selection and monitoring of suppliers;(e) the manufacturing process is systematically reviewed to ensure that it is capable of consistently delivering a product of the required quality in compliance with the relevant specifications and the terms of the marketing authorisation;(f) appropriate controls on intermediate products and any other in-process controls and validations are carried out;(g) veterinary medicinal products are not sold or supplied before a qualified person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorisation and in compliance with good manufacturing practice;(h) the results of product and process monitoring are taken into account in the context of batch release and in the investigation of deviations;(i) quality defects, deviations and other problems or unusual events that may have an impact on the quality of the veterinary medicinal product are identified as soon as possible, the causes investigated, and appropriate corrective and/or preventive measures are taken. The effectiveness of such measures shall be monitored and assessed;(j) arrangements are put in place for the prospective evaluation of planned changes and their approval prior to the implementation thereof taking into account applicable regulatory requirements, as well as for the evaluation of changes implemented (change control);(k) processes are implemented to ensure adequate management of outsourced activities;(l) knowledge related to the product and the manufacturing thereof is duly managed throughout the life-cycle of the veterinary medicinal product and in particular in the context of the transfer of activities and the implementation of changes to the manufacturing process or control procedures;(m) there is a process of self-inspection and/or quality audit which regularly appraises the effectiveness of the pharmaceutical quality system.

Article 6 Article 6 Product quality reviews 1.Product quality reviews shall be conducted and documented annually for each veterinary medicinal product, taking into account previous reviews, and shall include at least a review of the following elements: (a) materials used in the manufacturing process, especially those from new sources;(b) the supply chain traceability of active substances;(c) critical in-process controls and finished product results;(d) all batches that failed to meet established specification(s) and the investigation thereof;(e) significant deviations or non-conformances, the investigation thereof, and the effectiveness of resultant corrective and preventive actions taken;(f) changes carried out to the manufacturing process or analytical methods;(g) variations to the terms of the marketing authorisation affecting quality that have been submitted, granted or refused, as well as a review of post-marketing obligations affecting quality, including those relevant for veterinary medicinal products intended only for export;(h) the results of the stability monitoring programme and any adverse trends;(i) quality-related returns, complaints and recalls and the investigations performed at the time;(j) adequacy of any other previous product, process or equipment corrective actions;(k) the qualification status of relevant equipment and utilities, such as HVAC, water or compressed gases;(l) any contractual arrangements for outsourced activities to ensure that they are up to date. 2.Procedures shall be set for the conduct and evaluation of the product quality reviews and the effectiveness thereof shall be verified during the self-inspections referred to in Article 7. Product quality reviews may be grouped by product type (e.g. solid dosage forms, liquid dosage forms, sterile products), where scientifically justified. 3.The results of the product quality review shall be evaluated and it shall be assessed whether corrective and/or preventive actions or any revalidation is required. Where appropriate, opportunities for quality improvements shall be considered.

Article 7 Article 7 Self-inspection 1.Self-inspections shall be conducted to monitor the implementation of the arrangements regarding personnel, premises, equipment, documentation, production, quality control, batch release and arrangements to deal with quality-related complaints and recalls with the aim of verifying the suitability thereof to ensure that the veterinary medicinal products meet the required quality standards, and comply with the terms of the marketing authorisation and with good manufacturing practice. 2.Self-inspections shall be conducted at pre-defined intervals by individuals not involved in the audited activities. 3.Self-inspections shall be recorded. Reports shall include the observations made and, where applicable, proposals for corrective measures. The actions subsequently taken shall also be recorded.

Article 8 Article 8 Management review

Article 9 Article 9 General requirements for personnel 1.At each manufacturing site there shall be a sufficient number of personnel with the necessary qualifications and practical experience having regard to the intended operations. The individual responsibilities of personnel shall be clearly laid out. 2.Key personnel, including the qualified persons referred to in Article 97 of Regulation (EU) 2019/6, the head of production, the head of quality control and, where applicable, the head of quality assurance or the head of the quality unit shall be appointed by senior management. They shall be given sufficient resources to fulfil their duties. 3.The duties of the key personnel shall be clearly defined in job descriptions. The hierarchical relationships shall be set out in an organisation chart. There shall be no gaps or unexplained overlaps. The head of production shall assume responsibility for the activities set out in Chapter VI, as well as for the training of personnel and the qualification and maintenance of equipment and premises used for production. The head of quality control shall be responsible for the quality control operations set out in and for the training of personnel. 4.The heads of production and quality control shall be independent from each other. In large organisations, it may be necessary to delegate some of their tasks. However, such delegation of tasks shall not imply a delegation of responsibility. Additionally, depending on the size and organisational structure of the company, a separate head of quality assurance or head of the quality unit may be appointed. In that case, the responsibilities of the heads of production and quality control may be shared with the head of quality assurance or the head of the quality unit. 5.Consultants shall have adequate education, training and experience to advise on the subject for which they are retained. Records of the qualifications and type of service provided by consultants shall be kept.

(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;

Article 10 Article 10 Training 1.All personnel shall receive initial and continuous training relevant to the tasks assigned. Training on the pharmaceutical quality system and good manufacturing practice shall be provided for personnel whose duties take them into production and storage areas or into control laboratories, and for other personnel whose activities may have an impact on the quality of the product. Personnel working in areas where contamination is a hazard, such as clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, shall be given specific training. Training shall also include the hygiene programmes referred to in Article 11. 2.The practical effectiveness of training shall be periodically assessed. Records of the trainings shall be kept.

Article 11 Article 11 Hygiene 1.Detailed hygiene programmes adapted to the different needs within the manufacturing site shall be established. Such programmes shall include procedures relating to the health, hygiene practices and clothing of personnel. Particular attention shall be paid to hygiene measures necessary for the manufacture of sterile and biological preparations. Hygiene procedures shall be strictly followed by every person entering the production and control areas. 2.Personnel shall be offered a medical examination upon recruitment and subsequent health monitoring proportionate to the risks arising from the specific characteristics of the manufactured product and the tasks of the personnel. Personnel shall be encouraged to declare health conditions that can be of relevance to the quality of products to the manufacturer. 3.As far as possible, no person affected by an infectious disease or having open lesions on the exposed surface of the body shall be involved in the manufacture of veterinary medicinal products. 4.Every person entering the manufacturing areas shall wear protective clothing appropriate to the operations to be carried out, which shall be changed when appropriate. The clothing and its quality shall be appropriate for the process and the grade of the working area. It shall be worn in such a way as to protect the operator and the product from the risk of contamination. 5.Direct contact between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the product shall be avoided. 6.Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas shall be prohibited. Any unhygienic practice within the manufacturing area or in any other area where the product might be adversely affected shall also be prohibited. 7.Visitors or untrained personnel shall generally not be taken into the production or quality control areas. If this is unavoidable, visitors or untrained personnel shall be given information in advance, particularly about personal hygiene and the prescribed protective clothing, and they shall be closely supervised.

Article 12 Article 12 General requirements for premises 1.Premises used for the manufacture or import of veterinary medicinal products shall be suitable for the intended operations. In particular, the premises shall be designed or adapted, equipped, operated, cleaned and maintained to minimise the opportunity for extraneous contamination, cross-contamination, the risk of errors and any adverse effect on the quality of the products. 2.Premises shall be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Measures to prevent the entry of unauthorised people shall be implemented. 3.Production, storage and quality control areas shall not be used as a right of way by personnel not working in those areas.

Article 13 Article 13 Production areas 1.Cross-contamination shall be prevented by the appropriate design and operation of the premises. The measures to prevent cross-contamination shall be commensurate with the risks. Quality risk management principles shall be used to assess and control the risks. 2.Depending on the level of risk and based on the outcome of a quality risk management assessment, it may be necessary to dedicate premises and equipment for manufacturing or packaging operations to a particular product or product class. Dedicated premises shall be required when a risk cannot be adequately controlled by operational or technical measures. 3.The layout of the premises shall permit the production to take place in areas connected in a logical order corresponding to the sequence of the operations and the required level of cleanliness. 4.The arrangement of the working and in-process storage space shall be adequate to minimise the risk of confusion between different products or their components, to avoid cross-contamination, and to minimise the risk of omission or the wrong application of any of the manufacturing or control steps. 5.Where the materials used in the production of a veterinary medicinal product, an intermediate product or bulk product are exposed to the environment, the interior surfaces of the area (walls, floors and ceilings) shall be smooth, free from cracks and open joints, shall not shed particulate matter, and shall permit easy and effective cleaning and, if necessary, disinfection. 6.Pipework, light fittings, ventilation points and other services shall be designed and sited so as to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they shall be accessible from outside the manufacturing areas. 7.Drains shall be of adequate size and have trapped gullies. Open channels shall be avoided where possible but, where they are necessary, they shall be shallow to facilitate cleaning and disinfection. 8.Production areas shall be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate to the products handled, to the operations undertaken within them, and to the external environment. 9.In cases where dust is generated, such as during sampling, weighing, mixing and processing operations, or packaging of dry products, specific measures shall be implemented to avoid cross-contamination and to facilitate cleaning.

Article 14 Article 14 Quality control areas 1.Quality control areas shall generally be separated from production areas. Laboratories for the control of biologicals, microbiologicals and radioisotopes shall also be separated from each other. However, in-process controls may be carried out within the production area provided that they do not carry any risk for the products. 2.Quality control areas shall be designed to suit the operations to be carried out in those areas. Sufficient space shall be given to avoid mix-ups and cross-contamination during testing. Adequate storage space for samples and records shall be available. Separate rooms may also be required to protect sensitive instruments from vibration, electrical interference, humidity, or any other condition that may have a negative impact on their performance. 3.Special precautions shall be taken in quality control areas handling hazardous substances, such as biological samples.

Article 15 Article 15 Storage areas 1.Storage areas shall be of sufficient capacity to allow the orderly storage of the various categories of materials and products, including products in quarantine, and products released, rejected, returned or recalled. 2.Receiving and dispatch bays shall protect materials and products from the weather. Reception areas shall be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage. 3.Materials or products that present a specific risk shall be stored in safe and secure areas. 4.Where quarantine status is ensured by storage in separate areas, those areas shall be clearly marked and their access restricted to authorised personnel. Any system replacing a physical quarantine shall provide equivalent security. 5.Separate areas shall be provided for the storage of rejected, recalled or returned materials or products. Where sampling is conducted in the storage area, it shall be conducted in such a way as to prevent contamination or cross-contamination.

Article 16 Article 16 Ancillary areas 1.Rest and refreshment rooms shall be separate from production, storage and quality control areas. Toilets shall not directly communicate with production, storage or quality control areas. 2.Maintenance workshops shall -as far as possible- be separated from production areas. Whenever parts and tools are stored in the production area, they shall be kept in rooms or lockers reserved for that use. 3.Animals shall be kept in separated areas, with a separate entrance and air handling facilities.

Article 17 Article 17 Temperature and environmental controls 1.Lighting, temperature, humidity and ventilation conditions shall be appropriate and such that they do not adversely affect, directly or indirectly, the veterinary medicinal products during their manufacture and storage, or the accurate functioning of equipment. Where special conditions are required (e.g. temperature, humidity), these shall be specified and monitored. 2.Appropriate measures to monitor key environmental parameters shall be applied at the manufacturing site.

Article 18 Article 18 Equipment 1.Equipment used in production or control operations shall be suitable for its intended purpose and shall not present any hazard to the product. The parts of production equipment that come into contact with the product shall not have any unwanted reactive, additive, adsorptive or absorptive properties that may affect the quality of the product. 2.Equipment that is critical to the quality of the products shall be subject to appropriate qualification. 3.Balances and measuring equipment shall be of an appropriate range and precision to ensure the accuracy of weighing operations. 4.Equipment shall be operated and maintained in such a way as to minimise the risk of error and to avoid contamination, cross-contamination and, in general, any adverse effect on the quality of the product. 5.Equipment shall be calibrated, inspected or checked, as appropriate, at defined intervals to ensure an adequate performance. In the case of computerised systems, the checks shall include an evaluation of the ability of the system to ensure data integrity. Appropriate records of those checks shall be maintained. Additional requirements relevant to the use of computerised systems are laid down in Annex IV. 6.Equipment shall be adequately cleaned to avoid the risk of contamination for the products. The cleaning or decontamination procedures shall be detailed in writing, ensuring that the cleaning equipment does not become a source of contamination. Equipment shall only be stored in a clean and dry condition. 7.The location and installation of the equipment shall be adequate to minimise risks of errors or contamination. In general, equipment, including laboratory equipment, shall not be moved between high-risk areas. If equipment is moved between high-risk areas, appropriate measures shall be applied to avoid the risk of cross-contamination. Where appropriate, the qualification status of the equipment moved shall also be reconsidered. 8.Fixed pipework shall be clearly labelled to indicate the content and, where applicable, the direction of flow. 9.Water for pharmaceutical use and, where appropriate, other water pipes shall be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken. 10.Defective equipment shall be removed from production and quality control areas or, if the removal thereof is not possible, it shall be clearly labelled as defective.

Article 19 Article 19 Qualification of premises and equipment 1.Premises and equipment used in the manufacture of veterinary medicinal products, including utilities and systems, shall be qualified as appropriate to ensure that they are adequate for the intended operations. The qualification shall be performed in accordance with the requirements laid down in Annex V. 2.Decisions on the scope and extent of the qualification shall be based on a risk-assessment, which shall be documented. 3.Before starting the manufacture of a new type of veterinary medicinal product in premises that have already been qualified, the manufacturer shall assess if there is a need for re-qualification having regard to the specific risks and characteristics of the new manufacturing process or new product. 4.Premises and equipment shall be re-evaluated at appropriate intervals to confirm that they remain suitable for the intended operations.

(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;

Article 20 Article 20 Documentation system 1.A documentation system that is adequate to achieve the objectives of the pharmaceutical quality system shall be established and maintained. 2.The documentation system shall cover in a comprehensive matter the instructions and specifications as well as other documentation relevant to the pharmaceutical quality system and shall ensure that records of the activities which may, directly or indirectly, affect the quality of the veterinary medicinal products are kept. 3.The content of documents shall be unambiguous and be kept up to date. 4.Documentation may be kept in a variety of forms and the requirements set out in this Chapter are applicable irrespective of the form. Where electronic, photographic media, video recording or other data processing systems are used, the relevant systems shall be validated first to ensure that such systems are adequate to appropriately store the data during the required period of storage.

Article 21 Article 21 Specifications and instructions 1.Specifications and instructions shall be laid down in an orderly fashion and shall be clearly drafted. 2.The specifications for the materials used in the production of veterinary medicinal products and for the finished product, as well as the manufacturing instructions shall be adequate to ensure compliance with the terms of the marketing authorisation and the required level of quality. In particular, the following shall be duly documented: (a) specifications for active substances and other substances used in the manufacture of the veterinary medicinal product and for immediate packaging materials, including the following:a description of the active substances or other substances used, including any relevant information required to avoid risk of error (e.g. use of internal codes), and identification of the approved supplier(s). Where relevant, reference to a pharmacopeial monograph shall be provided; the quality and quantitative requirements as well as acceptance criteria, as appropriate; instructions for sampling and testing, as appropriate; storage conditions and, where applicable, any special handling precautions; the maximum period of storage; (b) specifications for intermediate products and bulk products, including release criteria and the maximum period of storage, shall be set out for critical stages and when those products are purchased or dispatched;(c) specifications for finished products, in particular:the name or identification of the product and, where applicable, the reference code; a description of the pharmaceutical form and packaging; instructions for sampling and testing; the qualitative and quantitative requirements with acceptance limits; storage conditions and, where applicable, any special handling precautions; the shelf-life; (d) manufacturing instructions (including a description of the principal equipment to be used) and in-process controls, including the following:the name of the product, with a product reference code relating to its specification; a description of the pharmaceutical form, strength of the product and batch size; a list of all materials to be used and the relevant amounts of each; an indication of the expected final yield with the acceptable limits and, where applicable, of relevant intermediate yields; an indication of the location where the relevant step should take place and the principal equipment to be used; an indication of or reference to the methods to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); detailed stepwise instructions to be followed (e.g. verification that equipment and workstation is clear of previous products, checks on materials, pre-treatments, sequence for adding materials, critical process parameters such as time, temperature, etc.); instructions for any in-process controls, together with their limits; where necessary, the requirements for bulk storage of the products, including the container, labelling and, where applicable, special storage conditions; any special precautions to be observed; (e) packaging instructions for each veterinary medicinal product and pack size, including:the name of the product as well as the batch number of the bulk product and finished product; a description of its pharmaceutical form, and strength where applicable; the pack size expressed in terms of the number, weight or volume of the product in the final container; a complete list of all the packaging materials required, including quantities, sizes and types, with the code or reference number relating to the specification of each packaging material; relevant instructions with an indication of the equipment to be used, and relevant precautions, including the need for a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; details of in-process controls with instructions for sampling and acceptance limits. 3.Documents containing specifications and instructions, including any changes thereto, shall be approved, signed and dated by authorised persons and the date of entry into operation shall be defined. Steps shall be taken to ensure that only the current version of a document is used.

Article 22 Article 22 Records 1.Adequate records shall be kept to enable the entire history of a batch to be traced. As a minimum, the following shall be documented: (a) receipt records for each delivery of materials used in the manufacture of the veterinary medicinal products including bulk products, intermediate products, and packaging materials. The receipt records shall include:the name of the material on the delivery note and the containers as well as any in-house name or internal code, if appropriate; the name of the supplier and manufacturer; the supplier’s batch or reference number; the total quantity and number of containers received; the date of receipt; the batch number assigned after receipt; any relevant comment; (b) a batch processing record which shall contain the following information:the name of the product and batch number; the dates and times of commencement, of critical intermediate stages, and of completion of production; the batch number or analytical control number and quantities actually weighed of each material used; an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person that checked these operations; a record of the in-process controls and the initials of the operator who carried them out; details of the manufacturing operations carried out and identification of major equipment used; the product yield obtained at relevant stages of manufacture; notes on any problems or unusual events that may impact on the quality of the product, including relevant details, with signed authorisation for any deviation from the manufacturing instructions; the approval of the batch processing record by the person responsible for the processing operations. Where a validated process is continuously monitored and controlled, the batch record may be limited to automatically generated reports with compliance summaries and exception or out-of- specification data reports; (c) a batch packaging record which shall contain the following information:the name of the product and batch number; the dates and times of the packaging operations; an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person who checked those operations; records of checks regarding the conformity with the packaging instructions, including the results of in-process controls; details of the packaging operations carried out and identification of major equipment and the packaging lines used; whenever possible, samples of printed packaging materials used, including the batch coding, expiry date and any additional overprinting; notes on any problems or unusual events that may have an impact on the quality of the product including details, with signed authorisation for any deviation from the packaging instructions; the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. This information may be omitted where electronic controls are in place; the approval of the batch packaging record by the person responsible for the packaging operations. 2.Records shall be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of veterinary medicinal products are traceable. 3.Logbooks shall be kept for major or critical analytical testing, for production equipment and for areas where a product has been processed. They shall be used to record in chronological order, as appropriate, any use of the area, equipment or method, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried out such operations. 4.Relevant records shall form the basis for assessment of the suitability for certification and release of a particular batch.

Article 23 Article 23 Other documentation 1.Policies and procedures applied to safeguard the quality of the product shall be duly documented, including the following: (a) training;(b) validation of manufacturing process and relevant analytical methods;(c) qualification of premises and equipment (including utilities and systems);(d) procedures or instructions for the handling of materials and products;(e) release and rejection procedures for materials and products;(f) cleaning procedures and the validation thereof, which shall be in accordance with the requirements laid down in Annex V;(g) procedures relating to quality control;(h) maintenance and calibration of equipment;(i) environmental monitoring;(j) investigations into deviations and non-conformances;(k) procedures for handling of quality-related complaints and recall or return of products;(l) procedures for handling changes to the manufacturing process (change control);(m) internal audits as well as audits of suppliers and sub-contractors;(n) technology transfer, where applicable. 2.Clear operating procedures shall be available for main manufacturing and test equipment. 3.A site master file shall be prepared for every manufacturing site involved in the manufacture of veterinary medicinal products, which shall provide a high-level description of the premises, of the activities conducted at the manufacturing site and of the quality system implemented. A model template is set out in Annex VI.

Article 24 Article 24 Retention periods 1.Batch documentation shall be kept for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the qualified person, whichever is longer. 2.Critical documentation that supports information in the marketing authorisation shall be retained whilst the authorisation remains in force, including relevant raw data such as data related to validation or stability. It may be considered acceptable to retire certain documentation, such as raw data supporting validation reports or stability reports, where the data has been superseded by a full set of new data. Justification for this shall be documented and shall take into account the requirements for retention of batch documentation. In the case of process validation data, the accompanying raw data shall be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise. 3.For other types of documentation, the retention period shall depend on the business activity which the documentation supports.

Article 25 Article 25 Data integrity 1.Suitable measures shall be implemented to ensure data integrity from the moment when data is generated and throughout the relevant retention period, including: (a) implementation of measures to protect data against accidental loss or damage by appropriate methods such as duplication or back-up and transfer to another storage system;(b) implementation of measures to protect data against tampering or unauthorised manipulation. In the case of computerised systems, suitable controls shall be put in place to limit access to authorised persons, such as the use of keys, pass cards, personal codes with passwords, biometrics or restricted access to computer equipment and data storage areas. The type of security controls shall be adapted to the criticality of the computerised system;(c) implementation of measures to ensure the accuracy, completeness, availability and legibility of documents throughout the retention period. Handwritten entries shall be made in a clear, legible and indelible way. The implemented measures shall be commensurate to the risks and the criticality of the data. 2.The issuance, revision, superseding and withdrawal of all documents shall be controlled by keeping a record of all revisions (revision histories). 3.Any alteration made to the entry on a document shall be signed and dated. The alteration shall permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded.

Article 26 Article 26 General requirements for production 1.Manufacturing operations (including packaging operations) and controls shall follow clearly defined procedures designed to ensure the quality of the product and compliance with the requirements set in the relevant manufacturing authorisation and marketing authorisation. 2.Manufacturing steps that may have an impact on the quality or reproducibility of the production, including significant changes thereto, shall be validated. Periodic re-validation shall be required to ensure that such manufacturing processes remain capable of achieving the intended results. Process validation shall comply with the requirements laid down in Annex V. 3.Manufacturing processes shall be duly documented and reviewed regularly, and they shall be improved as appropriate. The effects of changes to the manufacturing process on the quality of the finished product and in relation to the need to ensure consistent production shall be considered prior to the implementation of any changes. No change from the specifications and processes described in the dossier supporting the marketing authorisation shall be implemented before the relevant approval is obtained from the competent authorities, with the exception of variations not requiring assessment in accordance with Article 61 of Regulation (EU) 2019/6. 4.Adequate and sufficient resources shall be made available for the in-process controls. 5.Any deviation from instructions or procedures shall be avoided as far as possible. If a deviation occurs, it shall be approved in writing by a responsible person after having assessed the impact thereof on quality, safety and efficacy with the involvement of the qualified person as appropriate. Deviations shall be investigated to identify the root cause and to implement corrective and preventive measures as appropriate. 6.The manufacturer shall report to the marketing authorisation holder any constraints in manufacturing operations that may result in an abnormal restriction in the supply of the veterinary medicinal product.

Article 27 Article 27 Handling of materials and products 1.Handling of materials and products, including aspects related to the receipt, quarantine, sampling, storage, labelling and packaging, shall be done in accordance with written procedures or instructions and recorded as appropriate. 2.All incoming materials shall be checked to ensure that the consignment corresponds to the order. 3.Containers shall be cleaned where necessary. Damage to containers and any other problem (e.g. evidence of seal tampering or evidence of breaches of package integrity) that may adversely affect the quality of the material shall be investigated, recorded and reported to the department responsible for quality control. 4.Transport conditions for bulk products, intermediate products and samples shall be verified to ensure compliance with any specified conditions. 5.Incoming materials shall be physically or administratively quarantined immediately after receipt, until their release is authorised by a responsible person, after verification of compliance with the relevant specifications. If one material delivery is made up of different batches, each batch shall be considered separately for the purposes of sampling, testing and release. 6.All materials shall be stored under appropriate conditions to ensure the quality and in an orderly fashion to permit batch segregation (physical or electronic) and stock rotation. 7.Containers shall be labelled appropriately, including: (a) the designated name of the product and internal code reference, where applicable;(b) the batch number given at receipt;(c) where appropriate, the status of the content (e.g. in quarantine, on test, released, rejected);(d) where appropriate, an expiry date beyond which retesting is necessary. Where fully computerised storage systems are used, all the information referred to in points (a) to (d) does not need to appear in a legible form on the label. 8.At all times during the manufacturing process, all materials, bulk containers, major items of equipment and, where appropriate, rooms used shall be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable), and batch number. Where applicable, this indication shall also mention the stage of production. 9.Special precautions shall be taken when handling dry materials or products to prevent the generation and dissemination of dust, particularly for highly active or sensitising materials.

Article 28 Article 28 Qualification of suppliers and compliance with specifications 1.Suppliers of materials used in the manufacture of the veterinary medicinal product shall be approved after verifying the suitability thereof. In the case of critical materials, the qualification of the suppliers shall be required. The level of supervision of the suppliers shall be proportionate to the risks to the quality of the product posed by the individual materials. 2.The quality requirements (specifications) for the materials used in the manufacture of veterinary medicinal products shall be agreed with the supplier and documented. 3.Compliance with the requirements set out in the marketing authorisation shall be verified by means of appropriate testing. The level of supervision and further testing required shall be proportionate to the risks. The testing strategy shall be justified and, as a minimum, an identity check of each batch shall be performed by means of tests performed on samples taken from all the containers. Sampling a proportion of the containers shall only be acceptable when validated procedures based on quality risk management principles are in place to ensure the correct labelling of containers, and potential risks to the quality are addressed, for example through the qualification of the supplier. At appropriate intervals, having regard to the risks, a full analysis of the active substances and other critical materials shall be performed and the results shall be compared with the manufacturer or supplier’s certificate of analysis in order to check the reliability of the latter. The testing may be outsourced. If that testing identifies any discrepancy, an investigation shall be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier shall be discontinued until those measures are implemented. 4.Sufficient experience with the relevant supplier or manufacturer of active substances, including assessment of batches previously received and the history of compliance, shall be required before reducing the in-house testing. Any significant change in the manufacturing or testing processes of the active substances shall also be considered as a relevant factor. 5.Audits at the sites of manufacturers and distributors of active substances shall be conducted at appropriate intervals following a risk-based approach to confirm that they comply with good manufacturing practice and good distribution practice and with the specifications provided. Specific consideration shall be given to potential cross-contamination from other materials on site. Deficiencies shall be clearly identified and corrective and preventive actions shall be implemented as appropriate.

Article 29 Article 29 Prevention of cross-contamination 1.The production of non-medicinal products shall generally be avoided in areas and with equipment destined for the production of veterinary medicinal products, unless measures to prevent cross-contamination are applied in an effective manner. In particular, the production or storage of chemical substances used in biocides and plant protection products shall be avoided in areas used for the manufacture or storage of veterinary medicinal products, except where the same substance and its grade is also used for manufacture of veterinary medicinal products. 2.Where veterinary medicinal products are produced in an area shared with non-medicinal products, good manufacturing practice for medicinal products shall be implemented in the area. 3.Operations on different products shall not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination. 4.Before any manufacturing operation starts, steps shall be taken to ensure that the work area and the equipment are clean and free from any materials, products, product residues or documents not required for the current operation. Mix-ups of materials shall be prevented. 5.At every stage of production, products and materials shall be protected from microbial and other contamination. The risk of cross-contamination shall be assessed having regard to the characteristics of the product and the manufacturing process. The risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances or other materials used in the production, from residues on equipment and from operators’ clothing shall be assessed. 6.Measures to prevent cross-contamination identified on the basis of quality risk management principles shall be put in place. Measures that may be considered to prevent cross-contamination include: (a) the dedication of a whole manufacturing site or a self-contained production area on a campaign basis (separation in time) followed by a cleaning process of validated effectiveness;(b) the use of segregated areas;(c) the use of closed systems for processing and for material or product transfer;(d) the use of airlocks and pressure cascade to confine potential airborne contaminants within a specified area;(e) the use of physical barrier systems, including isolators, as containment measures;(f) the dedication of specific equipment or certain parts thereof (e.g. filters) to a given type of product with a specific risk profile;(g) the utilisation of single use disposable technologies;(h) the implementation of validated cleaning or decontamination procedures adapted to the specific characteristics of the product and of the manufacturing process. The cleaning or decontamination procedures that are necessary, including the frequency thereof, shall be determined on the basis of a risk-assessment;(i) other suitable organisational measures, such as keeping specific protective clothing inside areas where products at high-risk of contamination are processed, implementing adequate measures for the handling of waste, contaminated rinsing water and soiled gowning, or imposing restrictions on the movement of personnel. 7.The control strategy shall address all the potential risks, including measures at the level of the premises, equipment and personnel, controls on materials used in the manufacture, implementation of effective sterilisation and sanitisations procedures, and adequate monitoring systems. The totality of the measures applied shall ensure the absence of contamination of the products manufactured within the manufacturing site. Sole reliance shall not be placed on any terminal process or finished product test. 8.The effectiveness of the measures implemented shall be reviewed periodically according to set procedures. This assessment shall lead to the implementation of corrective and preventive actions where necessary.

(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;

Article 30 Article 30 Packaging operations 1.The name and batch number of the product being handled shall be displayed at each packaging station or line. 2.Containers for filling shall be clean before being filled. Filling and sealing shall be followed as quickly as possible by labelling. If it is not possible, appropriate procedures shall be applied to avoid mix-ups or mislabelling. 3.The correct performance of printing operations (for example code numbers, expiry dates) shall be checked and recorded. Printed and embossed information on packaging materials shall be clear and resistant to fade or erasure. 4.Checks shall be made to ensure that any electronic code readers, label counters or similar devices are operating correctly. 5.Appropriate measures shall be implemented to avoid mix ups, such as storing and transporting cut labels and other loose printed materials in separate closed containers. Special care shall be taken when using cut-labels and when over-printing is carried out off-line. To avoid mix-ups, roll-feed labels are generally preferable to cut-labels. 6.The following controls shall be performed on the product during packaging operations: (a) general appearance of the packages;(b) whether the packages are complete;(c) whether the correct products and packaging materials are used;(d) whether any over-printing is correct;(e) correct functioning of line monitors. Samples taken away from the packaging line shall not be returned. 7.Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and packaging materials and the number of units produced shall be investigated and resolved before the release of the product. 8.Outdated or obsolete immediate packaging material or printed packaging material shall be destroyed and such disposal recorded. A documented procedure shall be followed if un-coded printed materials are returned to stock.

Article 31 Article 31 Rejected, recovered and returned materials 1.Rejected materials shall be clearly marked as such and stored separately in restricted areas. They shall either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken, it shall be approved and recorded by authorised personnel. 2.The reprocessing of rejected materials can only be accepted exceptionally and provided that the quality of the final product is not affected and that the specifications set out in the marketing authorisation are met. The recovery of materials conforming to the required specifications from a distinct batch is only possible after an evaluation of the risks, including any possible effect on the shelf-life. Records shall be kept. 3.The need for additional testing of any finished product which has been reprocessed, or into which a reprocessed material has been incorporated, shall be evaluated by the quality control department. 4.Returned products, which have left the control of the manufacturer, shall be destroyed, unless their quality is confirmed by the quality control department. The nature of the product, its condition and history, any special storage conditions, and the time elapsed since it was issued shall be taken into account in that assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for re-issue or re-use. Any action taken shall be recorded.

Article 32 Article 32 Use of ionising radiation

Article 33 Article 33 General requirements for quality control 1.A quality control department independent from other departments shall be established and maintained. 2.The quality control department shall be allocated adequate resources, including regarding personnel, premises and equipment, to ensure that quality control can be effectively carried out having regard to the nature and size of the manufacturing operations. 3.The quality control department shall ensure that relevant tests are carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The quality control department is at least responsible for the following: (a) establishing, validating and implementing quality control procedures;(b) overseeing the control of the reference and retention samples of materials and products, where applicable;(c) ensuring the correct labelling of containers of materials and products;(d) ensuring the monitoring of the stability of the products;(e) participating in the investigation of complaints related to the quality of the product. All the activities referred to in the first subparagraph, points (a) to (e) shall be carried out in accordance with written procedures and, where necessary, recorded. 4.The head of quality control supervises all quality control procedures. In particular, it shall be responsible for the following tasks: (a) approval of specifications, sampling instructions, test methods and other quality control procedures;(b) ensuring that required testing is carried out and the associated records evaluated;(c) ensuring that the appropriate validations are done;(d) approval or rejection of materials used in production, intermediate products, bulk products and finished products;(e) ensuring the qualification and maintenance of the premises and equipment used for quality control;(f) approval and monitoring of any contract analysts. 5.Personnel involved in quality control shall have access to production areas and to all documents that are needed for the assessment of quality control, including: (a) specifications;(b) procedures describing sampling and testing;(c) testing reports and certificates of analysis;(d) procedures for calibration and qualification of instruments and maintenance of equipment and relevant records;(e) validation records of test methods, where applicable;(f) environmental monitoring data for air, water and other utilities, where required;(g) procedures for the investigation of out of specification and out of trend results. 6.Relevant quality control data, such as tests results, yields and environmental data, shall be assessed in a manner permitting trend evaluation. In the case of out of specifications or significant atypical trends, their possible impact on the batches on the market shall be assessed. Where following that assessment it is concluded that the quality of the marketed veterinary medicinal product may be impacted or that shortages of supply can be expected, the competent authorities shall be informed. 7.A quality control check shall be conducted before a finished veterinary medicinal product is released for sale or distribution. That check shall cover all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with the finished product specifications and examination of the final finished pack. 8.Quality control activities can be outsourced provided that the requirements set out in Article 43 are respected. Where tests on materials used in the manufacture of the veterinary medicinal products are outsourced, audits shall be performed by the manufacturer or via a third party to ensure compliance with relevant requirements of good manufacturing practice and the specifications or methods provided.

Article 34 Article 34 Sampling 1.A sampling plan shall be established, which shall take into account the risks to the quality of the veterinary medicinal product and address the different materials used in the manufacturing process as well as the various stages of production. 2.Samples shall be representative of the batch of materials or products from which they are taken. The sample taking shall be done in accordance with written procedures that describe at least the following: (a) the amount of sample to be taken;(b) equipment and containers to be used;(c) precautions to be observed to prevent contamination;(d) other precautions to be observed, in particular in the case of sterile or noxious materials;(e) storage conditions for the samples taken;(f) the cleaning instructions for the equipment used. 3.Personnel in charge of taking samples shall receive training on the following: (a) techniques and equipment for sampling;(b) the risks of cross-contamination;(c) precautions to be taken with regard to unstable or sterile substances;(d) the need to record any unexpected or unusual circumstance;(e) other aspects relevant to the implementation of the sampling procedures. 4.Sample containers shall bear a label indicating the content, batch number, date of sampling and containers from which the samples have been taken. When containers are too small, the use of bar-codes or other means that permit access to that information may be considered. Sample containers shall be handled and stored in a way that minimises the risk of mix-up or the deterioration of their content. The storage conditions set out in the marketing authorisation shall be applied. 5.Samples shall be kept at the disposal of the competent authorities for the following periods: (a) Reference samples and/or retention samples from each batch of finished product shall be retained for at least one year after the expiry date. The reference sample shall be contained in its finished immediate packaging.However, in the case of large volume presentations, where it is not feasible to retain samples from each batch in its final packaging, the manufacturer shall ensure that sufficient representative samples of each batch are retained and that the container used for storage is composed of the same material as the immediate container in which the product is marketed. (b) Reference samples of materials used in the manufacture of veterinary medicinal products, other than solvents, gases or water, shall be kept for at least two years after the release of the product. That period may be shortened if the period of stability of the material, as indicated in the relevant specification, is shorter.(c) Samples of packaging materials shall be kept for the duration of the shelf-life of the finished product concerned. For this purpose, retention of printed materials as part of the reference and/or retention samples is also acceptable. For finished products, reference and retention samples may be regarded as interchangeable. 6.Reference samples shall be of sufficient size to permit the carrying out on at least two occasions of the full analytical controls on the batch in accordance with the marketing authorisation. 7.In cases when the marketing authorisation holder is not the entity responsible for batch release or when several sites are responsible for the manufacture or batch release, the responsibility for the taking and storing of reference and retention samples shall be defined in writing. 8.The ability to do relevant testing throughout the shelf-life of the veterinary medicinal product shall be ensured.

Article 35 Article 35 Testing 1.Tests shall be performed to ensure that each batch of the finished product meets the relevant specifications and is in accordance with the terms of the marketing authorisation. Tests shall be performed at appropriate stages of production to control those conditions that are important for the quality of the product. Testing methods shall be validated. 2.The following records shall be kept in connection with the tests performed: (a) name of the material or product and, where applicable, dosage form;(b) batch number and, where appropriate, the manufacturer or supplier;(c) references to the relevant specifications and testing procedures;(d) test results, including observations and calculations, and reference to any certificates of analysis;(e) dates of testing;(f) identification of the persons who performed the testing;(g) identification of the persons who verified the testing and the calculations, where appropriate;(h) a clear statement of approval or rejection (or other status decision) and the dated signature of the responsible person;(i) reference to the equipment used. 3.Reference standards shall be suitable for their intended use. Their qualification or certification status shall be documented. Whenever compendial reference standards from an officially recognised source exist, these shall preferably be used as primary reference standards, unless duly justified. The use of secondary standards shall be documented and their traceability to primary standards shall be demonstrated. Compendial materials shall be used for the purpose described in the appropriate monograph unless otherwise authorised by the relevant competent authority. 4.Materials used for quality control tests, such as reagents, culture media, glassware, and reference standards shall be of appropriate quality and used according to the instructions of the manufacturer unless scientifically justified. The expiry date of reagents and culture media shall be indicated on the label, together with specific storage conditions. Where necessary, identity verification or testing shall be considered upon receipt or before use. 5.Where appropriate, animals used for testing components, materials or products shall be quarantined before use. They shall be maintained and controlled in a manner that assures their suitability for the intended use. In addition, they shall be identified and adequate records kept showing the history of their use. 6.Used microbiological media and strains shall be decontaminated in accordance with a standard procedure and disposed of in a manner to prevent cross-contamination.

Article 36 Article 36 On-going stability programme 1.After the marketing authorisation is granted, a programme shall be implemented to verify that, under the relevant storage conditions specified in the marketing authorisation and in the packaging as intended for marketing, the veterinary medicinal product remains within the specifications during the shelf-life (on-going stability programme). 2.The on-going stability programme shall be described in a written protocol which shall detail, among others, the number of batches, the test methods to be used, the acceptance criteria and the testing intervals. The methodology in the on-going stability programme can differ from the approach followed to obtain the stability data submitted in the marketing authorisation application (e.g. different frequency of testing), provided that it is justified. 3.The on-going stability studies shall generally be performed on the finished product as released by the manufacturer, unless a different approach is duly justified. When intermediate products or bulk products are stored for extended periods of time, consideration shall be given to include in the on-going stability programme those batches that have been manufactured from materials stored for longer periods of time. Stability studies on the reconstituted product need not be conducted as part of the on-going stability programme. 4.The number of batches and frequency of testing shall be adequate to allow for trend analysis and shall take into account the risks, such as significant changes in production, significant deviations, reworking or reprocessing operations. At least one batch of the product per strength and packaging type shall be included per year in the on-going stability programme, unless none are produced in a given year or a different frequency is otherwise justified. In particular, where the on-going stability monitoring requires testing using animals and no appropriate alternative techniques are available, the frequency of testing may be adapted. Bracketing and matrixing approaches may be applied if scientifically justified in the protocol. 5.Results of on-going stability studies shall be subject to periodic review and be made available to key personnel and, in particular, to the qualified person. A summary of all the data generated shall be kept.

Article 37 Article 37 Technical transfer of testing methods 1.Prior to transferring a test method, the transferring site shall verify that the test method complies with the terms of the marketing authorisation and relevant regulatory requirements. 2.The transfer of testing methods from one laboratory (transferring laboratory) to another laboratory (receiving laboratory) shall be described in a detailed protocol. 3.The protocol shall include, among others, the following elements: (a) identification of the testing to be performed and the relevant test method undergoing transfer;(b) identification of any specific training requirements;(c) identification of standards and samples to be tested;(d) identification of any special transport and storage conditions of test items;(e) the acceptance criteria. 4.Deviations from the protocol shall be investigated prior to the closure of the technical transfer process. The technical transfer report shall document the comparative outcome of the process and shall identify areas requiring further test method revalidation, if applicable.

Article 38 Article 38 Qualified person 1.Each manufacturing site of veterinary medicinal products in the Union shall have at least one qualified person. 2.To comply with the obligation set out under Article 97(6) of Regulation (EU) 2019/6, the qualified person shall, as a minimum, verify the following aspects: (a) the source and specifications for the materials used in the manufacture of veterinary medicinal products and the packaging materials comply with the terms of the marketing authorisation;(b) the active substances have been manufactured in accordance with good manufacturing practices and distributed in accordance with good distribution practice;(c) where applicable, the viral and microbial safety and TSE (transmissible spongiform encephalopathies) status of all materials used the manufacture is compliant with the terms of the marketing authorisation;(d) all manufacturing steps, including controls and testing, have been done in accordance with the marketing authorisation and at a manufacturing site authorised therein and in compliance with good manufacturing practice;(e) all required in-process controls and checks, including environmental monitoring, have been made and appropriate records exists;(f) finished product quality control test data shows compliance with the relevant specifications or, where applicable, the real time release testing programme;(g) on-going stability data continues to support certification;(h) the impact of any deviation to the manufacturing process or testing has been evaluated and any additional checks and tests are complete;(i) the impact of any change to the manufacturing process or testing has been evaluated and any additional checks and tests have been completed;(j) audits of manufacturing sites and sites involved in the manufacture or testing of the active substances support the certification of the batch;(k) measures related to the implementation of outsourced manufacture or testing, as provided for in the subcontracting arrangements, are in place;(l) all investigations on matters that may impact the quality of the batch being certified have been completed to a sufficient degree to support the certification of the batch;(m) the self-inspection programme is active. The qualified person, while being responsible for ensuring that the verifications set out in the first subparagraph are done, may delegate those tasks to appropriately trained personnel or third parties. 3.The qualified person shall have access to any documentation relevant to the steps for which he or she assumes responsibility, including details of the marketing authorisation necessary to assess if the relevant requirements have been complied with and relevant data about the entire manufacturing process of the veterinary medicinal product, including importation activities, if any. 4.Where more than one qualified person is involved in the assessment of one batch of a veterinary medicinal product, the division of responsibilities amongst them, including details on the responsibility for assessment of any deviations, shall be clearly laid down in writing. 5.The qualified person may rely on audits conducted by third parties attesting the compliance with good manufacturing practice in specific manufacturing sites. In such cases, the requirements in Article 43 shall apply. The qualified person shall have access to any documentation that is relevant to the review of the audit outcome. For the approval of the audit report, the qualified person shall take into consideration the following: (a) whether the audit report addresses general requirements of good manufacturing practice, such as the quality management system and production and quality control procedures related to the supplied product, with sufficient level of detail so as to allow a conclusion that the relevant activities covered by the audit comply with the marketing authorisation and good manufacturing practice;(b) in the case of outsourced activities, whether there has been verification of the compliance with the marketing authorisation and good manufacturing practice.

Article 39 Article 39 Certification and batch release 1.Batches of veterinary medicinal products can only be released for sale or supply to the market after a qualified person certifies – by means of a control report– that each batch of a veterinary medicinal product has been manufactured and tested in accordance with the requirements of the marketing authorisation and good manufacturing practice. Certification can only be performed by the qualified person of a manufacturer described in the marketing authorisation. A model template for batch release certificate is provided in Annex VIII. 2.Reliance by the qualified person on real time release testing or parametric release is only possible if the conditions and requirements laid down in Annex IX are met. 3.Evidence of the certification referred to in paragraph 1 shall be recorded by the qualified person in a register or equivalent document provided for that purpose. That register or equivalent document shall be kept up to date and shall remain at the disposal of the competent authority for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the qualified person, whichever is longer. 4.The qualified person who performs the certification of the batch of a veterinary medicinal product may assume full responsibility for all stages of manufacture of the batch or may share this responsibility with other qualified persons who have confirmed compliance of specific steps in the manufacture and control of a batch. If a manufacturing site only undertakes partial manufacturing operations, the qualified person at that site shall, at least, confirm that the operations undertaken at that manufacturing site have been performed in accordance with good manufacturing practice and the terms of the written agreement detailing the operations for which the manufacturing site is responsible. Partial manufacturing shall only occur in a manufacturing site authorised in accordance with the terms of the marketing authorisation. A model template for confirmation of partial manufacturing is provided in Annex VIII. 5.Where various batches of finished product originate from the same batch of bulk product, certification of the different batches of finished product may be based on the quality control testing of a previously certified batch provided that this is justified based on quality risk management principles. The following elements shall at least be verified by the qualified person: (a) the relevant requirements for storage of the bulk product prior to packaging have been complied with;(b) the batch of the finished product has been stored and, where applicable, transported under the required conditions;(c) the consignment has remained secure and there is no evidence of tampering during storage or transportation;(d) the identification of the product has been established;(e) the samples tested are representative of all finished product batches derived from the batch of bulk product. 6.Where the qualified person certifies a batch of a veterinary medicinal product in accordance with paragraph 1, he or she shall assign the release status to that batch by means of a formal and unambiguous notification to the manufacturing site releasing the product. 7.Pending the assignment of the release status referred to in paragraph 6, the batch shall remain at the manufacturing site or be shipped under quarantine to another manufacturing site authorised for that purpose. Safeguards to ensure that uncertified batches are not released shall be put in place. Those safeguards may be physical (by using segregation and labelling) or electronic (by using validated computerised systems). When uncertified batches are moved from one authorised manufacturing site to another, the safeguards to prevent premature release shall remain.

(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;

Article 40 Article 40 Additional considerations for imports of veterinary medicinal products 1.To comply with the obligation set out under Article 97(7) of Regulation (EU) 2019/6, the certification by the qualified person can only occur after a physical importation has taken place. The site of physical importation and the site of the qualified person responsible for the certification/confirmation shall be authorised in accordance with Article 88(1) of Regulation (EU) 2019/6. 2.Sampling of the imported product shall be fully representative of the batch. Samples required for the testing of the imported batch as well as reference and/or retention samples may either be taken after arrival in the Union or at the manufacturing site in the third country in accordance with a documented procedure. Responsibilities in relation to the sampling shall be defined in a written agreement between the manufacturing sites. Any samples taken outside the Union shall be shipped under equivalent transport conditions as the batch that they represent. 3.Where sampling is performed in a third country manufacturing site, the documented procedure referred to in paragraph 2 shall be justified in accordance with quality risk management principles and shall include at least the following elements: (a) audits of the manufacturing activities, including sampling, at the third country manufacturing site and evaluation of subsequent transportation steps of both the batch and samples to ensure that the samples are representative of the imported batch;(b) a comprehensive analysis supporting the conclusion that samples taken in the third country are representative of the batch after importation, including at least the following:a description of the sampling process; a description of the transport conditions of the sample and the imported batch; any differences shall be justified; comparative analysis of samples taken in the third country and samples taken after importation. In case of discrepancies or out of trends, these shall be documented and investigated; consideration of the time interval between sampling and importation of the batch and generation of data to support appropriate defined limits; (c) a random periodic analysis of samples taken after importation shall be performed to justify ongoing reliance on samples taken in a third country;(d) the conditions of storage and transport of the finished product and the samples, shall be checked before certifying any batch;(e) batch documentation supplied by the third country manufacturing site shall be in a format and language that is understandable for the importer;(f) relevant ordering and delivery documentation shall be available for inspection at the manufacturing site responsible for certification;(g) where batches are subdivided and partial quantities are imported separately, reconciliation of the quantities shall be verified and documented. Any discrepancy shall be investigated under the responsibility of the qualified person responsible for the certification of the batch;(h) the manufacturing site responsible for certification shall ensure that an ongoing stability programme is in place and that reference and retention samples have been taken. The ongoing stability programme may be carried out at the third country manufacturing site. 4.The manufacturing site responsible for certification shall qualify the third country manufacturer and conduct periodic monitoring, including by means of on-site audits, to ensure compliance with good manufacturing practice and the terms of the marketing authorisation.

Article 41 Article 41 Repackaging operations

Article 42 Article 42 Handling of unplanned deviations

Article 43 Article 43 Requirements for outsourced activities 1.The outsourcing of operations related to the manufacture or control of veterinary medicinal products shall be made by means of a written contract that provides for clear delineation of the responsibilities of each party. 2.The manufacturer (contract giver) shall assess the suitability of the contractor (contract acceptor) to carry out the outsourced activities. 3.The contract giver shall ensure that adequate information is transmitted to the contract acceptor for the performance of the outsourced activities and that the contract acceptor is aware of any problems associated with the product or the work that might pose a hazard to the premises, equipment, personnel, other materials or other products. 4.The following additional aspects shall be covered in the contract: (a) the contract acceptor shall comply with good manufacturing practice;(b) the contract acceptor shall permit audits or inspections by the contract giver and the competent authorities in connection with the outsourced activities;(c) all records related to the outsourced activities as well as the reference samples shall either be transferred to the contract giver or, in the alternative, the contract giver shall be granted access to them;(d) the contract acceptor shall not subcontract any of the work entrusted to him or her under the contract without written authorisation from the contract giver. 5.The contract giver shall review and assess the records and the results related to the outsourced activities and take relevant measures where appropriate.

Article 44 Article 44 Quality defects 1.A system shall be put in place to ensure that all quality-related complaints, whether received orally or in writing, are recorded and thoroughly investigated and that appropriate actions are implemented, including the recall of veterinary medicinal products where appropriate. 2.Personnel responsible for managing quality-related complaints and quality defect investigations shall be independent from marketing and sales departments unless otherwise justified. If the qualified person involved in the certification of the concerned batches does not participate in the investigation, it shall be informed in a timely manner. 3.Operating procedures shall be developed describing the actions to be taken upon the receipt of a quality-related complaint. Those operating procedures shall address at least the following: (a) the determination of the extent of quality defect;(b) the assessment of the risks posed by the quality defect;(c) the identification of the potential root causes of the quality defect or, where such route cause cannot be ascertained, the most probable reason;(d) the need for appropriate risk minimisation measures;(e) the need for corrective or preventive measures;(f) the assessment of the impact that any recall action may have on the availability of the veterinary medicinal product;(g) the internal and external communications to be made. 4.If the handling of quality-related complaints and suspected quality defects is managed centrally within an organisation, the relative roles and responsibilities of the parties concerned shall be documented. 5.If the veterinary medicinal product is manufactured by an entity that is not the marketing authorisation holder, the role and responsibilities of the manufacturer, the marketing authorisation holder and any other relevant third party shall be laid down in writing. 6.When a quality defect is discovered or suspected in a batch, consideration shall be given whether it is necessary to check other batches or, as appropriate, other products to determine if they are also affected. Batches that may contain portions of the defective batch or components shall be investigated. 7.Quality defect investigations shall include a review of previous quality defect reports or any other relevant information that is indicative of specific or recurring problems. 8.The priority during an investigation shall be to ensure that appropriate risk-minimisations measures are taken. All decisions and measures adopted shall reflect the level of risk and shall be documented. The effectiveness of the corrective and preventive measures implemented shall be monitored. 9.Quality defects shall be reported in a timely manner to the marketing authorisation holder. Competent authorities shall also be informed in the case of a confirmed quality defect that may result in the recall of the product or an abnormal restriction in the supply. Unplanned deviations as described in Article 42 need not be notified. 10.Measures to address quality defects shall be proportionate to the risks and the priority shall be the protection of treated animals and user safety. Wherever possible, the actions to be taken shall be discussed with the competent authorities concerned in advance.

Article 45 Article 45 Product recalls 1.Procedures for the recall of products shall be established, which shall include how a recall is to be initiated, who is to be informed in the event of a recall (including relevant authorities) and how the recalled material is to be treated. The respective role and tasks of the manufacturer and marketing authorisation holder regarding the initiation and organisation of recalls shall be clearly established. 2.It shall be ensured that recall operations can be initiated promptly and at any time. In certain cases, and with a view to protect the health of consumers or animals, it may be necessary to recall products prior to establishing the root cause or the full extent of the quality defect. 3.The effectiveness of the procedure for recalls shall be periodically evaluated, including during office hours and out-of-office hours. The possibility of performing mock-recall actions shall be considered and the outcome of this evaluation shall be documented. 4.Recalled products shall be identified and stored separately in a secure area while awaiting a decision on their fate. The progress of the recall shall be recorded until the recall procedure is closed and a final report is issued, including a reconciliation between the delivered and recovered quantities of the concerned products or batches. 5.All competent authorities concerned shall be informed prior to the initiation of a recall unless urgent action is required to protect the health of consumers or animals. The competent authorities shall also be informed in situations in which no recall action is being proposed for a defective batch because the batch has expired. 6.In addition to recalls, there are other risk-reducing actions that may be considered to manage the risks presented by quality defects, such as the transmission of appropriate information to healthcare professionals. Such course of action shall be discussed with and agreed by the competent authorities.

Article 46 Article 46 Entry into force and application

(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;

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.

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.

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.

The obligations of the marketing authorisation holder and the manufacturer and vis-à-vis each other shall be defined in writing.

Regulation (EU) No 910/2014 of the European Parliament and of the Council of 23 July 2014 on electronic identification and trust services for electronic transactions in the internal market and repealing Directive 1999/93/EC (OJ L 257, 28.8.2014, p. 73 , ELI: http://data.europa.eu/eli/reg/2014/910/oj).

(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;

Manufacturers shall have in place a comprehensive pharmaceutical quality system designed to ensure the quality of the veterinary medicinal products.

Compliance with good manufacturing practice and the terms of the marketing authorisation shall be an essential part of the pharmaceutical quality system.

(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;

(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 CouncilRegulation (EU) No 910/2014 of the European Parliament and of the Council of 23 July 2014 on electronic identification and trust services for electronic transactions in the internal market and repealing Directive 1999/93/EC (OJ L 257, 28.8.2014, p. 73 , ELI: http://data.europa.eu/eli/reg/2014/910/oj). .

The design of the pharmaceutical quality system shall be based on the following risk management principles:

(a) the evaluation of the risks to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the user and the safety of the animals treated;

(b) the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

While some aspects may be company-wide, the pharmaceutical quality system shall be developed and implemented at site level.

The size of the company and complexity of the relevant activities shall be taken into consideration in developing a pharmaceutical quality system or modifying an existing one. Senior management shall have the ultimate responsibility to ensure the effectiveness of the pharmaceutical quality system and, to that end, shall ensure that appropriate resources are allocated.

The pharmaceutical quality system shall be duly documented and the effectiveness thereof shall be monitored.

The pharmaceutical quality system shall ensure that:

(a) there is an adequate number of personnel with the necessary qualifications and adequate training and there is clear allocation of responsibilities, including managerial responsibilities;

(b) the premises and equipment are suitable for the intended use and they are appropriately maintained;

(c) there is an adequate documentation system that ensures that appropriate specifications are laid down for materials used in the manufacture of the veterinary medicinal product, intermediate product, bulk product and finished product, that the production and quality control procedures are clearly defined, and that appropriate records are kept;

(d) arrangements are put in place for the selection and monitoring of suppliers;

(e) the manufacturing process is systematically reviewed to ensure that it is capable of consistently delivering a product of the required quality in compliance with the relevant specifications and the terms of the marketing authorisation;

(f) appropriate controls on intermediate products and any other in-process controls and validations are carried out;

(g) veterinary medicinal products are not sold or supplied before a qualified person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorisation and in compliance with good manufacturing practice;

(h) the results of product and process monitoring are taken into account in the context of batch release and in the investigation of deviations;

(i) quality defects, deviations and other problems or unusual events that may have an impact on the quality of the veterinary medicinal product are identified as soon as possible, the causes investigated, and appropriate corrective and/or preventive measures are taken. The effectiveness of such measures shall be monitored and assessed;

(j) arrangements are put in place for the prospective evaluation of planned changes and their approval prior to the implementation thereof taking into account applicable regulatory requirements, as well as for the evaluation of changes implemented (change control);

(k) processes are implemented to ensure adequate management of outsourced activities;

(l) knowledge related to the product and the manufacturing thereof is duly managed throughout the life-cycle of the veterinary medicinal product and in particular in the context of the transfer of activities and the implementation of changes to the manufacturing process or control procedures;

(m) there is a process of self-inspection and/or quality audit which regularly appraises the effectiveness of the pharmaceutical quality system.

Product quality reviews shall be conducted and documented annually for each veterinary medicinal product, taking into account previous reviews, and shall include at least a review of the following elements:

(a) materials used in the manufacturing process, especially those from new sources;

(b) the supply chain traceability of active substances;

(c) critical in-process controls and finished product results;

(d) all batches that failed to meet established specification(s) and the investigation thereof;

(e) significant deviations or non-conformances, the investigation thereof, and the effectiveness of resultant corrective and preventive actions taken;

(f) changes carried out to the manufacturing process or analytical methods;

(g) variations to the terms of the marketing authorisation affecting quality that have been submitted, granted or refused, as well as a review of post-marketing obligations affecting quality, including those relevant for veterinary medicinal products intended only for export;

(h) the results of the stability monitoring programme and any adverse trends;

(i) quality-related returns, complaints and recalls and the investigations performed at the time;

(j) adequacy of any other previous product, process or equipment corrective actions;

(k) the qualification status of relevant equipment and utilities, such as HVAC, water or compressed gases;

(l) any contractual arrangements for outsourced activities to ensure that they are up to date.

Procedures shall be set for the conduct and evaluation of the product quality reviews and the effectiveness thereof shall be verified during the self-inspections referred to in Article 7. Product quality reviews may be grouped by product type (e.g. solid dosage forms, liquid dosage forms, sterile products), where scientifically justified.

The results of the product quality review shall be evaluated and it shall be assessed whether corrective and/or preventive actions or any revalidation is required. Where appropriate, opportunities for quality improvements shall be considered.

Self-inspections shall be conducted to monitor the implementation of the arrangements regarding personnel, premises, equipment, documentation, production, quality control, batch release and arrangements to deal with quality-related complaints and recalls with the aim of verifying the suitability thereof to ensure that the veterinary medicinal products meet the required quality standards, and comply with the terms of the marketing authorisation and with good manufacturing practice.

Self-inspections shall be conducted at pre-defined intervals by individuals not involved in the audited activities.

Self-inspections shall be recorded. Reports shall include the observations made and, where applicable, proposals for corrective measures. The actions subsequently taken shall also be recorded.

There shall be a periodic review of the operation of the pharmaceutical quality system with the involvement of senior management to identify opportunities for the improvement of the veterinary medicinal products, the manufacturing process and of the system itself.

At each manufacturing site there shall be a sufficient number of personnel with the necessary qualifications and practical experience having regard to the intended operations. The individual responsibilities of personnel shall be clearly laid out.

Key personnel, including the qualified persons referred to in Article 97 of Regulation (EU) 2019/6, the head of production, the head of quality control and, where applicable, the head of quality assurance or the head of the quality unit shall be appointed by senior management. They shall be given sufficient resources to fulfil their duties.

The duties of the key personnel shall be clearly defined in job descriptions. The hierarchical relationships shall be set out in an organisation chart. There shall be no gaps or unexplained overlaps. The head of production shall assume responsibility for the activities set out in Chapter VI, as well as for the training of personnel and the qualification and maintenance of equipment and premises used for production. The head of quality control shall be responsible for the quality control operations set out in and for the training of personnel.

The heads of production and quality control shall be independent from each other. In large organisations, it may be necessary to delegate some of their tasks. However, such delegation of tasks shall not imply a delegation of responsibility. Additionally, depending on the size and organisational structure of the company, a separate head of quality assurance or head of the quality unit may be appointed. In that case, the responsibilities of the heads of production and quality control may be shared with the head of quality assurance or the head of the quality unit.

Consultants shall have adequate education, training and experience to advise on the subject for which they are retained. Records of the qualifications and type of service provided by consultants shall be kept.

All personnel shall receive initial and continuous training relevant to the tasks assigned. Training on the pharmaceutical quality system and good manufacturing practice shall be provided for personnel whose duties take them into production and storage areas or into control laboratories, and for other personnel whose activities may have an impact on the quality of the product. Personnel working in areas where contamination is a hazard, such as clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, shall be given specific training. Training shall also include the hygiene programmes referred to in Article 11.

The practical effectiveness of training shall be periodically assessed. Records of the trainings shall be kept.

Detailed hygiene programmes adapted to the different needs within the manufacturing site shall be established. Such programmes shall include procedures relating to the health, hygiene practices and clothing of personnel. Particular attention shall be paid to hygiene measures necessary for the manufacture of sterile and biological preparations. Hygiene procedures shall be strictly followed by every person entering the production and control areas.

Personnel shall be offered a medical examination upon recruitment and subsequent health monitoring proportionate to the risks arising from the specific characteristics of the manufactured product and the tasks of the personnel. Personnel shall be encouraged to declare health conditions that can be of relevance to the quality of products to the manufacturer.

As far as possible, no person affected by an infectious disease or having open lesions on the exposed surface of the body shall be involved in the manufacture of veterinary medicinal products.

Every person entering the manufacturing areas shall wear protective clothing appropriate to the operations to be carried out, which shall be changed when appropriate. The clothing and its quality shall be appropriate for the process and the grade of the working area. It shall be worn in such a way as to protect the operator and the product from the risk of contamination.

Direct contact between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the product shall be avoided.

Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas shall be prohibited. Any unhygienic practice within the manufacturing area or in any other area where the product might be adversely affected shall also be prohibited.

Visitors or untrained personnel shall generally not be taken into the production or quality control areas. If this is unavoidable, visitors or untrained personnel shall be given information in advance, particularly about personal hygiene and the prescribed protective clothing, and they shall be closely supervised.

Premises used for the manufacture or import of veterinary medicinal products shall be suitable for the intended operations. In particular, the premises shall be designed or adapted, equipped, operated, cleaned and maintained to minimise the opportunity for extraneous contamination, cross-contamination, the risk of errors and any adverse effect on the quality of the products.

Premises shall be designed and equipped so as to afford maximum protection against the entry of insects or other animals. Measures to prevent the entry of unauthorised people shall be implemented.

Production, storage and quality control areas shall not be used as a right of way by personnel not working in those areas.

Cross-contamination shall be prevented by the appropriate design and operation of the premises. The measures to prevent cross-contamination shall be commensurate with the risks. Quality risk management principles shall be used to assess and control the risks.

Depending on the level of risk and based on the outcome of a quality risk management assessment, it may be necessary to dedicate premises and equipment for manufacturing or packaging operations to a particular product or product class. Dedicated premises shall be required when a risk cannot be adequately controlled by operational or technical measures.

The layout of the premises shall permit the production to take place in areas connected in a logical order corresponding to the sequence of the operations and the required level of cleanliness.

The arrangement of the working and in-process storage space shall be adequate to minimise the risk of confusion between different products or their components, to avoid cross-contamination, and to minimise the risk of omission or the wrong application of any of the manufacturing or control steps.

Where the materials used in the production of a veterinary medicinal product, an intermediate product or bulk product are exposed to the environment, the interior surfaces of the area (walls, floors and ceilings) shall be smooth, free from cracks and open joints, shall not shed particulate matter, and shall permit easy and effective cleaning and, if necessary, disinfection.

Pipework, light fittings, ventilation points and other services shall be designed and sited so as to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they shall be accessible from outside the manufacturing areas.

Drains shall be of adequate size and have trapped gullies. Open channels shall be avoided where possible but, where they are necessary, they shall be shallow to facilitate cleaning and disinfection.

Production areas shall be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate to the products handled, to the operations undertaken within them, and to the external environment.

In cases where dust is generated, such as during sampling, weighing, mixing and processing operations, or packaging of dry products, specific measures shall be implemented to avoid cross-contamination and to facilitate cleaning.

Quality control areas shall generally be separated from production areas. Laboratories for the control of biologicals, microbiologicals and radioisotopes shall also be separated from each other. However, in-process controls may be carried out within the production area provided that they do not carry any risk for the products.

Quality control areas shall be designed to suit the operations to be carried out in those areas. Sufficient space shall be given to avoid mix-ups and cross-contamination during testing. Adequate storage space for samples and records shall be available. Separate rooms may also be required to protect sensitive instruments from vibration, electrical interference, humidity, or any other condition that may have a negative impact on their performance.

Special precautions shall be taken in quality control areas handling hazardous substances, such as biological samples.

Storage areas shall be of sufficient capacity to allow the orderly storage of the various categories of materials and products, including products in quarantine, and products released, rejected, returned or recalled.

Receiving and dispatch bays shall protect materials and products from the weather. Reception areas shall be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

Materials or products that present a specific risk shall be stored in safe and secure areas.

Where quarantine status is ensured by storage in separate areas, those areas shall be clearly marked and their access restricted to authorised personnel. Any system replacing a physical quarantine shall provide equivalent security.

Separate areas shall be provided for the storage of rejected, recalled or returned materials or products. Where sampling is conducted in the storage area, it shall be conducted in such a way as to prevent contamination or cross-contamination.

Rest and refreshment rooms shall be separate from production, storage and quality control areas. Toilets shall not directly communicate with production, storage or quality control areas.

Maintenance workshops shall -as far as possible- be separated from production areas. Whenever parts and tools are stored in the production area, they shall be kept in rooms or lockers reserved for that use.

Animals shall be kept in separated areas, with a separate entrance and air handling facilities.

Lighting, temperature, humidity and ventilation conditions shall be appropriate and such that they do not adversely affect, directly or indirectly, the veterinary medicinal products during their manufacture and storage, or the accurate functioning of equipment. Where special conditions are required (e.g. temperature, humidity), these shall be specified and monitored.

Appropriate measures to monitor key environmental parameters shall be applied at the manufacturing site.

Equipment used in production or control operations shall be suitable for its intended purpose and shall not present any hazard to the product. The parts of production equipment that come into contact with the product shall not have any unwanted reactive, additive, adsorptive or absorptive properties that may affect the quality of the product.

Equipment that is critical to the quality of the products shall be subject to appropriate qualification.

Balances and measuring equipment shall be of an appropriate range and precision to ensure the accuracy of weighing operations.

Equipment shall be operated and maintained in such a way as to minimise the risk of error and to avoid contamination, cross-contamination and, in general, any adverse effect on the quality of the product.

Equipment shall be calibrated, inspected or checked, as appropriate, at defined intervals to ensure an adequate performance. In the case of computerised systems, the checks shall include an evaluation of the ability of the system to ensure data integrity. Appropriate records of those checks shall be maintained. Additional requirements relevant to the use of computerised systems are laid down in Annex IV.

Equipment shall be adequately cleaned to avoid the risk of contamination for the products. The cleaning or decontamination procedures shall be detailed in writing, ensuring that the cleaning equipment does not become a source of contamination. Equipment shall only be stored in a clean and dry condition.

The location and installation of the equipment shall be adequate to minimise risks of errors or contamination. In general, equipment, including laboratory equipment, shall not be moved between high-risk areas. If equipment is moved between high-risk areas, appropriate measures shall be applied to avoid the risk of cross-contamination. Where appropriate, the qualification status of the equipment moved shall also be reconsidered.

Fixed pipework shall be clearly labelled to indicate the content and, where applicable, the direction of flow.

Water for pharmaceutical use and, where appropriate, other water pipes shall be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

Defective equipment shall be removed from production and quality control areas or, if the removal thereof is not possible, it shall be clearly labelled as defective.

Premises and equipment used in the manufacture of veterinary medicinal products, including utilities and systems, shall be qualified as appropriate to ensure that they are adequate for the intended operations. The qualification shall be performed in accordance with the requirements laid down in Annex V.

Decisions on the scope and extent of the qualification shall be based on a risk-assessment, which shall be documented.

Before starting the manufacture of a new type of veterinary medicinal product in premises that have already been qualified, the manufacturer shall assess if there is a need for re-qualification having regard to the specific risks and characteristics of the new manufacturing process or new product.

Premises and equipment shall be re-evaluated at appropriate intervals to confirm that they remain suitable for the intended operations.

A documentation system that is adequate to achieve the objectives of the pharmaceutical quality system shall be established and maintained.

The documentation system shall cover in a comprehensive matter the instructions and specifications as well as other documentation relevant to the pharmaceutical quality system and shall ensure that records of the activities which may, directly or indirectly, affect the quality of the veterinary medicinal products are kept.

The content of documents shall be unambiguous and be kept up to date.

Documentation may be kept in a variety of forms and the requirements set out in this Chapter are applicable irrespective of the form. Where electronic, photographic media, video recording or other data processing systems are used, the relevant systems shall be validated first to ensure that such systems are adequate to appropriately store the data during the required period of storage.

Specifications and instructions shall be laid down in an orderly fashion and shall be clearly drafted.

The specifications for the materials used in the production of veterinary medicinal products and for the finished product, as well as the manufacturing instructions shall be adequate to ensure compliance with the terms of the marketing authorisation and the required level of quality. In particular, the following shall be duly documented:

(a) specifications for active substances and other substances used in the manufacture of the veterinary medicinal product and for immediate packaging materials, including the following:a description of the active substances or other substances used, including any relevant information required to avoid risk of error (e.g. use of internal codes), and identification of the approved supplier(s). Where relevant, reference to a pharmacopeial monograph shall be provided; the quality and quantitative requirements as well as acceptance criteria, as appropriate; instructions for sampling and testing, as appropriate; storage conditions and, where applicable, any special handling precautions; the maximum period of storage;

(b) specifications for intermediate products and bulk products, including release criteria and the maximum period of storage, shall be set out for critical stages and when those products are purchased or dispatched;

(c) specifications for finished products, in particular:the name or identification of the product and, where applicable, the reference code; a description of the pharmaceutical form and packaging; instructions for sampling and testing; the qualitative and quantitative requirements with acceptance limits; storage conditions and, where applicable, any special handling precautions; the shelf-life;

(d) manufacturing instructions (including a description of the principal equipment to be used) and in-process controls, including the following:the name of the product, with a product reference code relating to its specification; a description of the pharmaceutical form, strength of the product and batch size; a list of all materials to be used and the relevant amounts of each; an indication of the expected final yield with the acceptable limits and, where applicable, of relevant intermediate yields; an indication of the location where the relevant step should take place and the principal equipment to be used; an indication of or reference to the methods to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising); detailed stepwise instructions to be followed (e.g. verification that equipment and workstation is clear of previous products, checks on materials, pre-treatments, sequence for adding materials, critical process parameters such as time, temperature, etc.); instructions for any in-process controls, together with their limits; where necessary, the requirements for bulk storage of the products, including the container, labelling and, where applicable, special storage conditions; any special precautions to be observed;

(e) packaging instructions for each veterinary medicinal product and pack size, including:the name of the product as well as the batch number of the bulk product and finished product; a description of its pharmaceutical form, and strength where applicable; the pack size expressed in terms of the number, weight or volume of the product in the final container; a complete list of all the packaging materials required, including quantities, sizes and types, with the code or reference number relating to the specification of each packaging material; relevant instructions with an indication of the equipment to be used, and relevant precautions, including the need for a careful examination of the area and equipment in order to ascertain the line clearance before operations begin; details of in-process controls with instructions for sampling and acceptance limits.

Documents containing specifications and instructions, including any changes thereto, shall be approved, signed and dated by authorised persons and the date of entry into operation shall be defined. Steps shall be taken to ensure that only the current version of a document is used.

a description of the active substances or other substances used, including any relevant information required to avoid risk of error (e.g. use of internal codes), and identification of the approved supplier(s). Where relevant, reference to a pharmacopeial monograph shall be provided;

the name or identification of the product and, where applicable, the reference code;

the name of the product, with a product reference code relating to its specification;

the name of the product as well as the batch number of the bulk product and finished product;

the quality and quantitative requirements as well as acceptance criteria, as appropriate;

a description of the pharmaceutical form and packaging;

a description of the pharmaceutical form, strength of the product and batch size;

a description of its pharmaceutical form, and strength where applicable;

instructions for sampling and testing, as appropriate;

instructions for sampling and testing;

a list of all materials to be used and the relevant amounts of each;

the pack size expressed in terms of the number, weight or volume of the product in the final container;

storage conditions and, where applicable, any special handling precautions;

the qualitative and quantitative requirements with acceptance limits;

an indication of the expected final yield with the acceptable limits and, where applicable, of relevant intermediate yields;

a complete list of all the packaging materials required, including quantities, sizes and types, with the code or reference number relating to the specification of each packaging material;

the maximum period of storage;

storage conditions and, where applicable, any special handling precautions;

an indication of the location where the relevant step should take place and the principal equipment to be used;

relevant instructions with an indication of the equipment to be used, and relevant precautions, including the need for a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;

the shelf-life;

an indication of or reference to the methods to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising);

details of in-process controls with instructions for sampling and acceptance limits.

detailed stepwise instructions to be followed (e.g. verification that equipment and workstation is clear of previous products, checks on materials, pre-treatments, sequence for adding materials, critical process parameters such as time, temperature, etc.);

instructions for any in-process controls, together with their limits;

where necessary, the requirements for bulk storage of the products, including the container, labelling and, where applicable, special storage conditions;

any special precautions to be observed;

Adequate records shall be kept to enable the entire history of a batch to be traced. As a minimum, the following shall be documented:

(a) receipt records for each delivery of materials used in the manufacture of the veterinary medicinal products including bulk products, intermediate products, and packaging materials. The receipt records shall include:the name of the material on the delivery note and the containers as well as any in-house name or internal code, if appropriate; the name of the supplier and manufacturer; the supplier’s batch or reference number; the total quantity and number of containers received; the date of receipt; the batch number assigned after receipt; any relevant comment;

(b) a batch processing record which shall contain the following information:the name of the product and batch number; the dates and times of commencement, of critical intermediate stages, and of completion of production; the batch number or analytical control number and quantities actually weighed of each material used; an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person that checked these operations; a record of the in-process controls and the initials of the operator who carried them out; details of the manufacturing operations carried out and identification of major equipment used; the product yield obtained at relevant stages of manufacture; notes on any problems or unusual events that may impact on the quality of the product, including relevant details, with signed authorisation for any deviation from the manufacturing instructions; the approval of the batch processing record by the person responsible for the processing operations. Where a validated process is continuously monitored and controlled, the batch record may be limited to automatically generated reports with compliance summaries and exception or out-of- specification data reports;

(c) a batch packaging record which shall contain the following information:the name of the product and batch number; the dates and times of the packaging operations; an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person who checked those operations; records of checks regarding the conformity with the packaging instructions, including the results of in-process controls; details of the packaging operations carried out and identification of major equipment and the packaging lines used; whenever possible, samples of printed packaging materials used, including the batch coding, expiry date and any additional overprinting; notes on any problems or unusual events that may have an impact on the quality of the product including details, with signed authorisation for any deviation from the packaging instructions; the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. This information may be omitted where electronic controls are in place; the approval of the batch packaging record by the person responsible for the packaging operations.

Records shall be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of veterinary medicinal products are traceable.

Logbooks shall be kept for major or critical analytical testing, for production equipment and for areas where a product has been processed. They shall be used to record in chronological order, as appropriate, any use of the area, equipment or method, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried out such operations.

Relevant records shall form the basis for assessment of the suitability for certification and release of a particular batch.

the name of the material on the delivery note and the containers as well as any in-house name or internal code, if appropriate;

the name of the product and batch number;

the name of the product and batch number;

the name of the supplier and manufacturer;

the dates and times of commencement, of critical intermediate stages, and of completion of production;

the dates and times of the packaging operations;

the supplier’s batch or reference number;

the batch number or analytical control number and quantities actually weighed of each material used;

an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person who checked those operations;

the total quantity and number of containers received;

an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person that checked these operations;

records of checks regarding the conformity with the packaging instructions, including the results of in-process controls;

the date of receipt;

a record of the in-process controls and the initials of the operator who carried them out;

details of the packaging operations carried out and identification of major equipment and the packaging lines used;

the batch number assigned after receipt;

details of the manufacturing operations carried out and identification of major equipment used;

whenever possible, samples of printed packaging materials used, including the batch coding, expiry date and any additional overprinting;

any relevant comment;

the product yield obtained at relevant stages of manufacture;

notes on any problems or unusual events that may have an impact on the quality of the product including details, with signed authorisation for any deviation from the packaging instructions;

notes on any problems or unusual events that may impact on the quality of the product, including relevant details, with signed authorisation for any deviation from the manufacturing instructions;

the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. This information may be omitted where electronic controls are in place;

the approval of the batch processing record by the person responsible for the processing operations.

the approval of the batch packaging record by the person responsible for the packaging operations.

Policies and procedures applied to safeguard the quality of the product shall be duly documented, including the following:

(a) training;

(b) validation of manufacturing process and relevant analytical methods;

(c) qualification of premises and equipment (including utilities and systems);

(d) procedures or instructions for the handling of materials and products;

(e) release and rejection procedures for materials and products;

(f) cleaning procedures and the validation thereof, which shall be in accordance with the requirements laid down in Annex V;

(g) procedures relating to quality control;

(h) maintenance and calibration of equipment;

(i) environmental monitoring;

(j) investigations into deviations and non-conformances;

(k) procedures for handling of quality-related complaints and recall or return of products;

(l) procedures for handling changes to the manufacturing process (change control);

(m) internal audits as well as audits of suppliers and sub-contractors;

(n) technology transfer, where applicable.

Clear operating procedures shall be available for main manufacturing and test equipment.

A site master file shall be prepared for every manufacturing site involved in the manufacture of veterinary medicinal products, which shall provide a high-level description of the premises, of the activities conducted at the manufacturing site and of the quality system implemented. A model template is set out in Annex VI.

Batch documentation shall be kept for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the qualified person, whichever is longer.

Critical documentation that supports information in the marketing authorisation shall be retained whilst the authorisation remains in force, including relevant raw data such as data related to validation or stability. It may be considered acceptable to retire certain documentation, such as raw data supporting validation reports or stability reports, where the data has been superseded by a full set of new data. Justification for this shall be documented and shall take into account the requirements for retention of batch documentation. In the case of process validation data, the accompanying raw data shall be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise.

For other types of documentation, the retention period shall depend on the business activity which the documentation supports.

Suitable measures shall be implemented to ensure data integrity from the moment when data is generated and throughout the relevant retention period, including:

(a) implementation of measures to protect data against accidental loss or damage by appropriate methods such as duplication or back-up and transfer to another storage system;

(b) implementation of measures to protect data against tampering or unauthorised manipulation. In the case of computerised systems, suitable controls shall be put in place to limit access to authorised persons, such as the use of keys, pass cards, personal codes with passwords, biometrics or restricted access to computer equipment and data storage areas. The type of security controls shall be adapted to the criticality of the computerised system;

(c) implementation of measures to ensure the accuracy, completeness, availability and legibility of documents throughout the retention period. Handwritten entries shall be made in a clear, legible and indelible way.

The implemented measures shall be commensurate to the risks and the criticality of the data.

The issuance, revision, superseding and withdrawal of all documents shall be controlled by keeping a record of all revisions (revision histories).

Any alteration made to the entry on a document shall be signed and dated. The alteration shall permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded.

Manufacturing operations (including packaging operations) and controls shall follow clearly defined procedures designed to ensure the quality of the product and compliance with the requirements set in the relevant manufacturing authorisation and marketing authorisation.

Manufacturing steps that may have an impact on the quality or reproducibility of the production, including significant changes thereto, shall be validated. Periodic re-validation shall be required to ensure that such manufacturing processes remain capable of achieving the intended results. Process validation shall comply with the requirements laid down in Annex V.

Manufacturing processes shall be duly documented and reviewed regularly, and they shall be improved as appropriate. The effects of changes to the manufacturing process on the quality of the finished product and in relation to the need to ensure consistent production shall be considered prior to the implementation of any changes. No change from the specifications and processes described in the dossier supporting the marketing authorisation shall be implemented before the relevant approval is obtained from the competent authorities, with the exception of variations not requiring assessment in accordance with Article 61 of Regulation (EU) 2019/6.

Adequate and sufficient resources shall be made available for the in-process controls.

Any deviation from instructions or procedures shall be avoided as far as possible. If a deviation occurs, it shall be approved in writing by a responsible person after having assessed the impact thereof on quality, safety and efficacy with the involvement of the qualified person as appropriate. Deviations shall be investigated to identify the root cause and to implement corrective and preventive measures as appropriate.

The manufacturer shall report to the marketing authorisation holder any constraints in manufacturing operations that may result in an abnormal restriction in the supply of the veterinary medicinal product.

Handling of materials and products, including aspects related to the receipt, quarantine, sampling, storage, labelling and packaging, shall be done in accordance with written procedures or instructions and recorded as appropriate.

All incoming materials shall be checked to ensure that the consignment corresponds to the order.

Containers shall be cleaned where necessary. Damage to containers and any other problem (e.g. evidence of seal tampering or evidence of breaches of package integrity) that may adversely affect the quality of the material shall be investigated, recorded and reported to the department responsible for quality control.

Transport conditions for bulk products, intermediate products and samples shall be verified to ensure compliance with any specified conditions.

Incoming materials shall be physically or administratively quarantined immediately after receipt, until their release is authorised by a responsible person, after verification of compliance with the relevant specifications. If one material delivery is made up of different batches, each batch shall be considered separately for the purposes of sampling, testing and release.

All materials shall be stored under appropriate conditions to ensure the quality and in an orderly fashion to permit batch segregation (physical or electronic) and stock rotation.

Containers shall be labelled appropriately, including:

(a) the designated name of the product and internal code reference, where applicable;

(b) the batch number given at receipt;

(c) where appropriate, the status of the content (e.g. in quarantine, on test, released, rejected);

(d) where appropriate, an expiry date beyond which retesting is necessary.

Where fully computerised storage systems are used, all the information referred to in points (a) to (d) does not need to appear in a legible form on the label.

At all times during the manufacturing process, all materials, bulk containers, major items of equipment and, where appropriate, rooms used shall be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable), and batch number. Where applicable, this indication shall also mention the stage of production.

Special precautions shall be taken when handling dry materials or products to prevent the generation and dissemination of dust, particularly for highly active or sensitising materials.

Suppliers of materials used in the manufacture of the veterinary medicinal product shall be approved after verifying the suitability thereof. In the case of critical materials, the qualification of the suppliers shall be required. The level of supervision of the suppliers shall be proportionate to the risks to the quality of the product posed by the individual materials.

The quality requirements (specifications) for the materials used in the manufacture of veterinary medicinal products shall be agreed with the supplier and documented.

Compliance with the requirements set out in the marketing authorisation shall be verified by means of appropriate testing. The level of supervision and further testing required shall be proportionate to the risks. The testing strategy shall be justified and, as a minimum, an identity check of each batch shall be performed by means of tests performed on samples taken from all the containers. Sampling a proportion of the containers shall only be acceptable when validated procedures based on quality risk management principles are in place to ensure the correct labelling of containers, and potential risks to the quality are addressed, for example through the qualification of the supplier.

At appropriate intervals, having regard to the risks, a full analysis of the active substances and other critical materials shall be performed and the results shall be compared with the manufacturer or supplier’s certificate of analysis in order to check the reliability of the latter. The testing may be outsourced. If that testing identifies any discrepancy, an investigation shall be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier shall be discontinued until those measures are implemented.

Sufficient experience with the relevant supplier or manufacturer of active substances, including assessment of batches previously received and the history of compliance, shall be required before reducing the in-house testing. Any significant change in the manufacturing or testing processes of the active substances shall also be considered as a relevant factor.

Audits at the sites of manufacturers and distributors of active substances shall be conducted at appropriate intervals following a risk-based approach to confirm that they comply with good manufacturing practice and good distribution practice and with the specifications provided. Specific consideration shall be given to potential cross-contamination from other materials on site. Deficiencies shall be clearly identified and corrective and preventive actions shall be implemented as appropriate.

The production of non-medicinal products shall generally be avoided in areas and with equipment destined for the production of veterinary medicinal products, unless measures to prevent cross-contamination are applied in an effective manner. In particular, the production or storage of chemical substances used in biocides and plant protection products shall be avoided in areas used for the manufacture or storage of veterinary medicinal products, except where the same substance and its grade is also used for manufacture of veterinary medicinal products.

Where veterinary medicinal products are produced in an area shared with non-medicinal products, good manufacturing practice for medicinal products shall be implemented in the area.

Operations on different products shall not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.

Before any manufacturing operation starts, steps shall be taken to ensure that the work area and the equipment are clean and free from any materials, products, product residues or documents not required for the current operation. Mix-ups of materials shall be prevented.

At every stage of production, products and materials shall be protected from microbial and other contamination. The risk of cross-contamination shall be assessed having regard to the characteristics of the product and the manufacturing process. The risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances or other materials used in the production, from residues on equipment and from operators’ clothing shall be assessed.

Measures to prevent cross-contamination identified on the basis of quality risk management principles shall be put in place. Measures that may be considered to prevent cross-contamination include:

(a) the dedication of a whole manufacturing site or a self-contained production area on a campaign basis (separation in time) followed by a cleaning process of validated effectiveness;

(b) the use of segregated areas;

(c) the use of closed systems for processing and for material or product transfer;

(d) the use of airlocks and pressure cascade to confine potential airborne contaminants within a specified area;

(e) the use of physical barrier systems, including isolators, as containment measures;

(f) the dedication of specific equipment or certain parts thereof (e.g. filters) to a given type of product with a specific risk profile;

(g) the utilisation of single use disposable technologies;

(h) the implementation of validated cleaning or decontamination procedures adapted to the specific characteristics of the product and of the manufacturing process. The cleaning or decontamination procedures that are necessary, including the frequency thereof, shall be determined on the basis of a risk-assessment;

(i) other suitable organisational measures, such as keeping specific protective clothing inside areas where products at high-risk of contamination are processed, implementing adequate measures for the handling of waste, contaminated rinsing water and soiled gowning, or imposing restrictions on the movement of personnel.

The control strategy shall address all the potential risks, including measures at the level of the premises, equipment and personnel, controls on materials used in the manufacture, implementation of effective sterilisation and sanitisations procedures, and adequate monitoring systems. The totality of the measures applied shall ensure the absence of contamination of the products manufactured within the manufacturing site. Sole reliance shall not be placed on any terminal process or finished product test.

The effectiveness of the measures implemented shall be reviewed periodically according to set procedures. This assessment shall lead to the implementation of corrective and preventive actions where necessary.

The name and batch number of the product being handled shall be displayed at each packaging station or line.

Containers for filling shall be clean before being filled. Filling and sealing shall be followed as quickly as possible by labelling. If it is not possible, appropriate procedures shall be applied to avoid mix-ups or mislabelling.

The correct performance of printing operations (for example code numbers, expiry dates) shall be checked and recorded. Printed and embossed information on packaging materials shall be clear and resistant to fade or erasure.

Checks shall be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.

Appropriate measures shall be implemented to avoid mix ups, such as storing and transporting cut labels and other loose printed materials in separate closed containers. Special care shall be taken when using cut-labels and when over-printing is carried out off-line. To avoid mix-ups, roll-feed labels are generally preferable to cut-labels.

The following controls shall be performed on the product during packaging operations:

(a) general appearance of the packages;

(b) whether the packages are complete;

(c) whether the correct products and packaging materials are used;

(d) whether any over-printing is correct;

(e) correct functioning of line monitors.

Samples taken away from the packaging line shall not be returned.

Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and packaging materials and the number of units produced shall be investigated and resolved before the release of the product.

Outdated or obsolete immediate packaging material or printed packaging material shall be destroyed and such disposal recorded. A documented procedure shall be followed if un-coded printed materials are returned to stock.

Rejected materials shall be clearly marked as such and stored separately in restricted areas. They shall either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken, it shall be approved and recorded by authorised personnel.

The reprocessing of rejected materials can only be accepted exceptionally and provided that the quality of the final product is not affected and that the specifications set out in the marketing authorisation are met. The recovery of materials conforming to the required specifications from a distinct batch is only possible after an evaluation of the risks, including any possible effect on the shelf-life. Records shall be kept.

The need for additional testing of any finished product which has been reprocessed, or into which a reprocessed material has been incorporated, shall be evaluated by the quality control department.

Returned products, which have left the control of the manufacturer, shall be destroyed, unless their quality is confirmed by the quality control department. The nature of the product, its condition and history, any special storage conditions, and the time elapsed since it was issued shall be taken into account in that assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for re-issue or re-use. Any action taken shall be recorded.

The use of ionising radiation in the manufacture of veterinary medicinal products shall comply with the additional requirements set out in Annex VII.

A quality control department independent from other departments shall be established and maintained.

The quality control department shall be allocated adequate resources, including regarding personnel, premises and equipment, to ensure that quality control can be effectively carried out having regard to the nature and size of the manufacturing operations.

The quality control department shall ensure that relevant tests are carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The quality control department is at least responsible for the following:

(a) establishing, validating and implementing quality control procedures;

(b) overseeing the control of the reference and retention samples of materials and products, where applicable;

(c) ensuring the correct labelling of containers of materials and products;

(d) ensuring the monitoring of the stability of the products;

(e) participating in the investigation of complaints related to the quality of the product.

All the activities referred to in the first subparagraph, points (a) to (e) shall be carried out in accordance with written procedures and, where necessary, recorded.

The head of quality control supervises all quality control procedures. In particular, it shall be responsible for the following tasks:

(a) approval of specifications, sampling instructions, test methods and other quality control procedures;

(b) ensuring that required testing is carried out and the associated records evaluated;

(c) ensuring that the appropriate validations are done;

(d) approval or rejection of materials used in production, intermediate products, bulk products and finished products;

(e) ensuring the qualification and maintenance of the premises and equipment used for quality control;

(f) approval and monitoring of any contract analysts.

Personnel involved in quality control shall have access to production areas and to all documents that are needed for the assessment of quality control, including:

(a) specifications;

(b) procedures describing sampling and testing;

(c) testing reports and certificates of analysis;

(d) procedures for calibration and qualification of instruments and maintenance of equipment and relevant records;

(e) validation records of test methods, where applicable;

(f) environmental monitoring data for air, water and other utilities, where required;

(g) procedures for the investigation of out of specification and out of trend results.

Relevant quality control data, such as tests results, yields and environmental data, shall be assessed in a manner permitting trend evaluation. In the case of out of specifications or significant atypical trends, their possible impact on the batches on the market shall be assessed. Where following that assessment it is concluded that the quality of the marketed veterinary medicinal product may be impacted or that shortages of supply can be expected, the competent authorities shall be informed.

A quality control check shall be conducted before a finished veterinary medicinal product is released for sale or distribution. That check shall cover all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with the finished product specifications and examination of the final finished pack.

Quality control activities can be outsourced provided that the requirements set out in Article 43 are respected. Where tests on materials used in the manufacture of the veterinary medicinal products are outsourced, audits shall be performed by the manufacturer or via a third party to ensure compliance with relevant requirements of good manufacturing practice and the specifications or methods provided.

A sampling plan shall be established, which shall take into account the risks to the quality of the veterinary medicinal product and address the different materials used in the manufacturing process as well as the various stages of production.

Samples shall be representative of the batch of materials or products from which they are taken. The sample taking shall be done in accordance with written procedures that describe at least the following:

(a) the amount of sample to be taken;

(b) equipment and containers to be used;

(c) precautions to be observed to prevent contamination;

(d) other precautions to be observed, in particular in the case of sterile or noxious materials;

(e) storage conditions for the samples taken;

(f) the cleaning instructions for the equipment used.

Personnel in charge of taking samples shall receive training on the following:

(a) techniques and equipment for sampling;

(b) the risks of cross-contamination;

(c) precautions to be taken with regard to unstable or sterile substances;

(d) the need to record any unexpected or unusual circumstance;

(e) other aspects relevant to the implementation of the sampling procedures.

Sample containers shall bear a label indicating the content, batch number, date of sampling and containers from which the samples have been taken. When containers are too small, the use of bar-codes or other means that permit access to that information may be considered.

Sample containers shall be handled and stored in a way that minimises the risk of mix-up or the deterioration of their content. The storage conditions set out in the marketing authorisation shall be applied.

Samples shall be kept at the disposal of the competent authorities for the following periods:

(a) Reference samples and/or retention samples from each batch of finished product shall be retained for at least one year after the expiry date. The reference sample shall be contained in its finished immediate packaging.However, in the case of large volume presentations, where it is not feasible to retain samples from each batch in its final packaging, the manufacturer shall ensure that sufficient representative samples of each batch are retained and that the container used for storage is composed of the same material as the immediate container in which the product is marketed.

(b) Reference samples of materials used in the manufacture of veterinary medicinal products, other than solvents, gases or water, shall be kept for at least two years after the release of the product. That period may be shortened if the period of stability of the material, as indicated in the relevant specification, is shorter.

(c) Samples of packaging materials shall be kept for the duration of the shelf-life of the finished product concerned. For this purpose, retention of printed materials as part of the reference and/or retention samples is also acceptable.

For finished products, reference and retention samples may be regarded as interchangeable.

Reference samples shall be of sufficient size to permit the carrying out on at least two occasions of the full analytical controls on the batch in accordance with the marketing authorisation.

In cases when the marketing authorisation holder is not the entity responsible for batch release or when several sites are responsible for the manufacture or batch release, the responsibility for the taking and storing of reference and retention samples shall be defined in writing.

The ability to do relevant testing throughout the shelf-life of the veterinary medicinal product shall be ensured.

Tests shall be performed to ensure that each batch of the finished product meets the relevant specifications and is in accordance with the terms of the marketing authorisation. Tests shall be performed at appropriate stages of production to control those conditions that are important for the quality of the product. Testing methods shall be validated.

The following records shall be kept in connection with the tests performed:

(a) name of the material or product and, where applicable, dosage form;

(b) batch number and, where appropriate, the manufacturer or supplier;

(c) references to the relevant specifications and testing procedures;

(d) test results, including observations and calculations, and reference to any certificates of analysis;

(e) dates of testing;

(f) identification of the persons who performed the testing;

(g) identification of the persons who verified the testing and the calculations, where appropriate;

(h) a clear statement of approval or rejection (or other status decision) and the dated signature of the responsible person;

(i) reference to the equipment used.

Reference standards shall be suitable for their intended use. Their qualification or certification status shall be documented. Whenever compendial reference standards from an officially recognised source exist, these shall preferably be used as primary reference standards, unless duly justified. The use of secondary standards shall be documented and their traceability to primary standards shall be demonstrated. Compendial materials shall be used for the purpose described in the appropriate monograph unless otherwise authorised by the relevant competent authority.

Materials used for quality control tests, such as reagents, culture media, glassware, and reference standards shall be of appropriate quality and used according to the instructions of the manufacturer unless scientifically justified. The expiry date of reagents and culture media shall be indicated on the label, together with specific storage conditions. Where necessary, identity verification or testing shall be considered upon receipt or before use.

Where appropriate, animals used for testing components, materials or products shall be quarantined before use. They shall be maintained and controlled in a manner that assures their suitability for the intended use. In addition, they shall be identified and adequate records kept showing the history of their use.

Used microbiological media and strains shall be decontaminated in accordance with a standard procedure and disposed of in a manner to prevent cross-contamination.

After the marketing authorisation is granted, a programme shall be implemented to verify that, under the relevant storage conditions specified in the marketing authorisation and in the packaging as intended for marketing, the veterinary medicinal product remains within the specifications during the shelf-life (on-going stability programme).

The on-going stability programme shall be described in a written protocol which shall detail, among others, the number of batches, the test methods to be used, the acceptance criteria and the testing intervals. The methodology in the on-going stability programme can differ from the approach followed to obtain the stability data submitted in the marketing authorisation application (e.g. different frequency of testing), provided that it is justified.

The on-going stability studies shall generally be performed on the finished product as released by the manufacturer, unless a different approach is duly justified. When intermediate products or bulk products are stored for extended periods of time, consideration shall be given to include in the on-going stability programme those batches that have been manufactured from materials stored for longer periods of time. Stability studies on the reconstituted product need not be conducted as part of the on-going stability programme.

The number of batches and frequency of testing shall be adequate to allow for trend analysis and shall take into account the risks, such as significant changes in production, significant deviations, reworking or reprocessing operations. At least one batch of the product per strength and packaging type shall be included per year in the on-going stability programme, unless none are produced in a given year or a different frequency is otherwise justified. In particular, where the on-going stability monitoring requires testing using animals and no appropriate alternative techniques are available, the frequency of testing may be adapted. Bracketing and matrixing approaches may be applied if scientifically justified in the protocol.

Results of on-going stability studies shall be subject to periodic review and be made available to key personnel and, in particular, to the qualified person. A summary of all the data generated shall be kept.

Prior to transferring a test method, the transferring site shall verify that the test method complies with the terms of the marketing authorisation and relevant regulatory requirements.

The transfer of testing methods from one laboratory (transferring laboratory) to another laboratory (receiving laboratory) shall be described in a detailed protocol.

The protocol shall include, among others, the following elements:

(a) identification of the testing to be performed and the relevant test method undergoing transfer;

(b) identification of any specific training requirements;

(c) identification of standards and samples to be tested;

(d) identification of any special transport and storage conditions of test items;

(e) the acceptance criteria.

Deviations from the protocol shall be investigated prior to the closure of the technical transfer process. The technical transfer report shall document the comparative outcome of the process and shall identify areas requiring further test method revalidation, if applicable.

Each manufacturing site of veterinary medicinal products in the Union shall have at least one qualified person.

To comply with the obligation set out under Article 97(6) of Regulation (EU) 2019/6, the qualified person shall, as a minimum, verify the following aspects:

(a) the source and specifications for the materials used in the manufacture of veterinary medicinal products and the packaging materials comply with the terms of the marketing authorisation;

(b) the active substances have been manufactured in accordance with good manufacturing practices and distributed in accordance with good distribution practice;

(c) where applicable, the viral and microbial safety and TSE (transmissible spongiform encephalopathies) status of all materials used the manufacture is compliant with the terms of the marketing authorisation;

(d) all manufacturing steps, including controls and testing, have been done in accordance with the marketing authorisation and at a manufacturing site authorised therein and in compliance with good manufacturing practice;

(e) all required in-process controls and checks, including environmental monitoring, have been made and appropriate records exists;

(f) finished product quality control test data shows compliance with the relevant specifications or, where applicable, the real time release testing programme;

(g) on-going stability data continues to support certification;

(h) the impact of any deviation to the manufacturing process or testing has been evaluated and any additional checks and tests are complete;

(i) the impact of any change to the manufacturing process or testing has been evaluated and any additional checks and tests have been completed;

(j) audits of manufacturing sites and sites involved in the manufacture or testing of the active substances support the certification of the batch;

(k) measures related to the implementation of outsourced manufacture or testing, as provided for in the subcontracting arrangements, are in place;

(l) all investigations on matters that may impact the quality of the batch being certified have been completed to a sufficient degree to support the certification of the batch;

(m) the self-inspection programme is active.

The qualified person, while being responsible for ensuring that the verifications set out in the first subparagraph are done, may delegate those tasks to appropriately trained personnel or third parties.

The qualified person shall have access to any documentation relevant to the steps for which he or she assumes responsibility, including details of the marketing authorisation necessary to assess if the relevant requirements have been complied with and relevant data about the entire manufacturing process of the veterinary medicinal product, including importation activities, if any.

Where more than one qualified person is involved in the assessment of one batch of a veterinary medicinal product, the division of responsibilities amongst them, including details on the responsibility for assessment of any deviations, shall be clearly laid down in writing.

The qualified person may rely on audits conducted by third parties attesting the compliance with good manufacturing practice in specific manufacturing sites. In such cases, the requirements in Article 43 shall apply. The qualified person shall have access to any documentation that is relevant to the review of the audit outcome.

For the approval of the audit report, the qualified person shall take into consideration the following:

(a) whether the audit report addresses general requirements of good manufacturing practice, such as the quality management system and production and quality control procedures related to the supplied product, with sufficient level of detail so as to allow a conclusion that the relevant activities covered by the audit comply with the marketing authorisation and good manufacturing practice;

(b) in the case of outsourced activities, whether there has been verification of the compliance with the marketing authorisation and good manufacturing practice.

Batches of veterinary medicinal products can only be released for sale or supply to the market after a qualified person certifies – by means of a control report– that each batch of a veterinary medicinal product has been manufactured and tested in accordance with the requirements of the marketing authorisation and good manufacturing practice. Certification can only be performed by the qualified person of a manufacturer described in the marketing authorisation. A model template for batch release certificate is provided in Annex VIII.

Reliance by the qualified person on real time release testing or parametric release is only possible if the conditions and requirements laid down in Annex IX are met.

Evidence of the certification referred to in paragraph 1 shall be recorded by the qualified person in a register or equivalent document provided for that purpose. That register or equivalent document shall be kept up to date and shall remain at the disposal of the competent authority for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the qualified person, whichever is longer.

The qualified person who performs the certification of the batch of a veterinary medicinal product may assume full responsibility for all stages of manufacture of the batch or may share this responsibility with other qualified persons who have confirmed compliance of specific steps in the manufacture and control of a batch.

If a manufacturing site only undertakes partial manufacturing operations, the qualified person at that site shall, at least, confirm that the operations undertaken at that manufacturing site have been performed in accordance with good manufacturing practice and the terms of the written agreement detailing the operations for which the manufacturing site is responsible. Partial manufacturing shall only occur in a manufacturing site authorised in accordance with the terms of the marketing authorisation. A model template for confirmation of partial manufacturing is provided in Annex VIII.

Where various batches of finished product originate from the same batch of bulk product, certification of the different batches of finished product may be based on the quality control testing of a previously certified batch provided that this is justified based on quality risk management principles. The following elements shall at least be verified by the qualified person:

(a) the relevant requirements for storage of the bulk product prior to packaging have been complied with;

(b) the batch of the finished product has been stored and, where applicable, transported under the required conditions;

(c) the consignment has remained secure and there is no evidence of tampering during storage or transportation;

(d) the identification of the product has been established;

(e) the samples tested are representative of all finished product batches derived from the batch of bulk product.

Where the qualified person certifies a batch of a veterinary medicinal product in accordance with paragraph 1, he or she shall assign the release status to that batch by means of a formal and unambiguous notification to the manufacturing site releasing the product.

Pending the assignment of the release status referred to in paragraph 6, the batch shall remain at the manufacturing site or be shipped under quarantine to another manufacturing site authorised for that purpose. Safeguards to ensure that uncertified batches are not released shall be put in place. Those safeguards may be physical (by using segregation and labelling) or electronic (by using validated computerised systems). When uncertified batches are moved from one authorised manufacturing site to another, the safeguards to prevent premature release shall remain.

To comply with the obligation set out under Article 97(7) of Regulation (EU) 2019/6, the certification by the qualified person can only occur after a physical importation has taken place. The site of physical importation and the site of the qualified person responsible for the certification/confirmation shall be authorised in accordance with Article 88(1) of Regulation (EU) 2019/6.

Sampling of the imported product shall be fully representative of the batch. Samples required for the testing of the imported batch as well as reference and/or retention samples may either be taken after arrival in the Union or at the manufacturing site in the third country in accordance with a documented procedure. Responsibilities in relation to the sampling shall be defined in a written agreement between the manufacturing sites. Any samples taken outside the Union shall be shipped under equivalent transport conditions as the batch that they represent.

Where sampling is performed in a third country manufacturing site, the documented procedure referred to in paragraph 2 shall be justified in accordance with quality risk management principles and shall include at least the following elements:

(a) audits of the manufacturing activities, including sampling, at the third country manufacturing site and evaluation of subsequent transportation steps of both the batch and samples to ensure that the samples are representative of the imported batch;

(b) a comprehensive analysis supporting the conclusion that samples taken in the third country are representative of the batch after importation, including at least the following:a description of the sampling process; a description of the transport conditions of the sample and the imported batch; any differences shall be justified; comparative analysis of samples taken in the third country and samples taken after importation. In case of discrepancies or out of trends, these shall be documented and investigated; consideration of the time interval between sampling and importation of the batch and generation of data to support appropriate defined limits;

(c) a random periodic analysis of samples taken after importation shall be performed to justify ongoing reliance on samples taken in a third country;

(d) the conditions of storage and transport of the finished product and the samples, shall be checked before certifying any batch;

(e) batch documentation supplied by the third country manufacturing site shall be in a format and language that is understandable for the importer;

(f) relevant ordering and delivery documentation shall be available for inspection at the manufacturing site responsible for certification;

(g) where batches are subdivided and partial quantities are imported separately, reconciliation of the quantities shall be verified and documented. Any discrepancy shall be investigated under the responsibility of the qualified person responsible for the certification of the batch;

(h) the manufacturing site responsible for certification shall ensure that an ongoing stability programme is in place and that reference and retention samples have been taken. The ongoing stability programme may be carried out at the third country manufacturing site.

The manufacturing site responsible for certification shall qualify the third country manufacturer and conduct periodic monitoring, including by means of on-site audits, to ensure compliance with good manufacturing practice and the terms of the marketing authorisation.

a description of the sampling process;

a description of the transport conditions of the sample and the imported batch; any differences shall be justified;

comparative analysis of samples taken in the third country and samples taken after importation. In case of discrepancies or out of trends, these shall be documented and investigated;

consideration of the time interval between sampling and importation of the batch and generation of data to support appropriate defined limits;

The qualified person of a manufacturing site that is only involved in repackaging operations shall certify that the repackaging has been done in compliance with relevant good manufacturing practice requirements.

Where an unplanned deviation related to the manufacturing process or the analytical control methods has occurred, a qualified person may confirm compliance or certify the batch only if the following conditions are met:

(a) the specifications for active substances, excipients, packaging materials and finished product are complied with;

(b) there is an in-depth assessment of the impact of the deviation which supports a conclusion that the occurrence does not have a negative effect on quality, safety or efficacy of the product;

(c) where appropriate, the need for inclusion of the affected batch/batches in the on-going stability programme has been evaluated.

The outsourcing of operations related to the manufacture or control of veterinary medicinal products shall be made by means of a written contract that provides for clear delineation of the responsibilities of each party.

The manufacturer (contract giver) shall assess the suitability of the contractor (contract acceptor) to carry out the outsourced activities.

The contract giver shall ensure that adequate information is transmitted to the contract acceptor for the performance of the outsourced activities and that the contract acceptor is aware of any problems associated with the product or the work that might pose a hazard to the premises, equipment, personnel, other materials or other products.

The following additional aspects shall be covered in the contract:

(a) the contract acceptor shall comply with good manufacturing practice;

(b) the contract acceptor shall permit audits or inspections by the contract giver and the competent authorities in connection with the outsourced activities;

(c) all records related to the outsourced activities as well as the reference samples shall either be transferred to the contract giver or, in the alternative, the contract giver shall be granted access to them;

(d) the contract acceptor shall not subcontract any of the work entrusted to him or her under the contract without written authorisation from the contract giver.

The contract giver shall review and assess the records and the results related to the outsourced activities and take relevant measures where appropriate.

A system shall be put in place to ensure that all quality-related complaints, whether received orally or in writing, are recorded and thoroughly investigated and that appropriate actions are implemented, including the recall of veterinary medicinal products where appropriate.

Personnel responsible for managing quality-related complaints and quality defect investigations shall be independent from marketing and sales departments unless otherwise justified. If the qualified person involved in the certification of the concerned batches does not participate in the investigation, it shall be informed in a timely manner.

Operating procedures shall be developed describing the actions to be taken upon the receipt of a quality-related complaint. Those operating procedures shall address at least the following:

(a) the determination of the extent of quality defect;

(b) the assessment of the risks posed by the quality defect;

(c) the identification of the potential root causes of the quality defect or, where such route cause cannot be ascertained, the most probable reason;

(d) the need for appropriate risk minimisation measures;

(e) the need for corrective or preventive measures;

(f) the assessment of the impact that any recall action may have on the availability of the veterinary medicinal product;

(g) the internal and external communications to be made.

If the handling of quality-related complaints and suspected quality defects is managed centrally within an organisation, the relative roles and responsibilities of the parties concerned shall be documented.

If the veterinary medicinal product is manufactured by an entity that is not the marketing authorisation holder, the role and responsibilities of the manufacturer, the marketing authorisation holder and any other relevant third party shall be laid down in writing.

When a quality defect is discovered or suspected in a batch, consideration shall be given whether it is necessary to check other batches or, as appropriate, other products to determine if they are also affected. Batches that may contain portions of the defective batch or components shall be investigated.

Quality defect investigations shall include a review of previous quality defect reports or any other relevant information that is indicative of specific or recurring problems.

The priority during an investigation shall be to ensure that appropriate risk-minimisations measures are taken. All decisions and measures adopted shall reflect the level of risk and shall be documented. The effectiveness of the corrective and preventive measures implemented shall be monitored.

Quality defects shall be reported in a timely manner to the marketing authorisation holder. Competent authorities shall also be informed in the case of a confirmed quality defect that may result in the recall of the product or an abnormal restriction in the supply. Unplanned deviations as described in Article 42 need not be notified.

Measures to address quality defects shall be proportionate to the risks and the priority shall be the protection of treated animals and user safety. Wherever possible, the actions to be taken shall be discussed with the competent authorities concerned in advance.

Procedures for the recall of products shall be established, which shall include how a recall is to be initiated, who is to be informed in the event of a recall (including relevant authorities) and how the recalled material is to be treated. The respective role and tasks of the manufacturer and marketing authorisation holder regarding the initiation and organisation of recalls shall be clearly established.

It shall be ensured that recall operations can be initiated promptly and at any time. In certain cases, and with a view to protect the health of consumers or animals, it may be necessary to recall products prior to establishing the root cause or the full extent of the quality defect.

The effectiveness of the procedure for recalls shall be periodically evaluated, including during office hours and out-of-office hours. The possibility of performing mock-recall actions shall be considered and the outcome of this evaluation shall be documented.

Recalled products shall be identified and stored separately in a secure area while awaiting a decision on their fate. The progress of the recall shall be recorded until the recall procedure is closed and a final report is issued, including a reconciliation between the delivered and recovered quantities of the concerned products or batches.

All competent authorities concerned shall be informed prior to the initiation of a recall unless urgent action is required to protect the health of consumers or animals. The competent authorities shall also be informed in situations in which no recall action is being proposed for a defective batch because the batch has expired.

In addition to recalls, there are other risk-reducing actions that may be considered to manage the risks presented by quality defects, such as the transmission of appropriate information to healthcare professionals. Such course of action shall be discussed with and agreed by the competent authorities.

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union .

It shall apply from 16 July 2026 .

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