Commission Implementing Regulation (EU) 2025/2091 of 17 October 2025 laying down good manufacturing practice for veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council

• — the proposed real time measurement and control of the relevant in-process material attributes and process parameters shall be accurate predictors of the corresponding finished product attributes;

• — the suitability of the combination of the relevant assessed material attributes and process controls to replace end-product testing shall be scientifically demonstrated;

• — the combined process measurements (process parameters and material attributes) and any other test data generated during the manufacturing process shall provide a robust basis for the batch release decision.

• I.3.A real time release testing strategy shall be integrated and controlled as part of the pharmaceutical quality system, in particular with respect to:

• (a) personnel: the implementation of real time release testing requires input from a cross-functional/multi-disciplinary team with relevant experience on topics, such as engineering, analytics, chemometric modelling or statistics;

• (b) control strategy: when implementing real time release testing, it is paramount to ensure the robustness of controls applied during the manufacturing process and their suitability to ensure the quality of the product and consistent production. The control strategy shall be adapted through the life-cycle in light of acquired knowledge and in accordance with quality risk management principles;

• (c) management of changes: requirements set forth in Article 26(3) are particularly relevant when implementing real time release testing;

• (d) validation and qualification policy: the qualification and validation of in-line ([^E0090]) and on-line ([^E0091]) analytical methods is particularly relevant when real time release testing is implemented, especially when advanced analytical methods are used. Particular attention shall be paid to the location where the sampling probe is placed within the manufacturing equipment;

• (e) any deviation or process failure shall be thoroughly investigated and any adverse trending indicating a change in the state of control of the process, equipment or facilities shall be followed up appropriately;

• (f) continuous learning through data collection and analysis over the life cycle of a product is important. Manufacturers shall scientifically evaluate data (including data trends), to assess opportunities to improve quality and/or consistency. For the implementation of changes, Article 26(3) applies.

• I.4.When real time release testing has been approved in the marketing authorisation, this approach shall be routinely used for batch release and may not be replaced by end-product testing (unless the terms of the marketing authorisation are amended). In the event that the results from real time release testing fail or are trending toward failure, there shall be a thorough investigation. The results of the investigation shall be duly considered for a decision on batch release (release may only take place if it is ascertained that the product complies with the terms of the marketing authorisation and good manufacturing practice). Trends shall be followed up appropriately.

• I.5.Attributes (e.g. uniformity of content) that are indirectly controlled by approved real time release testing shall appear in the certificate of analysis for batches. The approved method for end-product testing shall be mentioned and the results given as ‘Complies if tested’ with a footnote: ‘Controlled by approved real time release testing’.

II.   PARAMETRIC RELEASE

• II.1.Parametric release for terminally sterilised products is the release of a batch based on a review of critical process control parameters instead of relying on end-product testing for sterility. Requirements set forth in Annex I regarding terminal sterilisation shall apply.

• II.2.An end-product test for sterility is limited in its ability to detect contamination as it utilises only a small number of samples in relation to the overall batch size, and also because culture media may only stimulate growth of some, but not all, microorganisms. Therefore, an end-product testing for sterility only provides an opportunity to detect major failures in the sterility assurance system (i.e. a failure that results in the contamination of a large number of product units or that result in contamination by the specific microorganisms whose growth is supported by the prescribed media). In contrast, data derived from in-process controls (e.g. pre-sterilisation product bioburden or environmental monitoring) and by monitoring relevant sterilisation parameters can provide more accurate and relevant information to support sterility assurance of the product.

• II.3.Parametric release may only be applied to products sterilised in their final container using either moist heat, dry heat or ionising radiation (dosimetric release), according to European Pharmacopoeial requirements. Additionally, it is required that the manufacturer has a good record of compliance with good manufacturing practice and a robust sterility assurance programme in place to demonstrate a consistent process control and process understanding.

• II.4.The sterility assurance programme shall be documented and include, at least, the identification and monitoring of the critical process parameters, the steriliser cycle development and the validation thereof, the container/packaging integrity validation, the bioburden control, the environmental monitoring programme and relevant aspects concerning personnel, premises, equipment and utilities.

• II.5.Risk management is an essential aspect of parametric release and shall focus on mitigating the factors that increase the risk of failure to achieve and maintain sterility in each unit of every batch. If a new product or process is being considered for parametric release, a risk assessment shall be conducted during the process development, including an evaluation of production data from existing products if applicable. If an existing product or process is being considered, the risk assessment shall include an evaluation of historical data.

• II.6.Personnel involved in the parametric release process shall have experience in the following areas: microbiology, sterility assurance, engineering, production and sterilisation. The qualifications, experience and training of personnel involved in parametric release shall be documented.

• II.7.Any proposed change that may impact on sterility assurance shall be handled in accordance with Article 26(3) by appropriate personnel who are qualified and experienced in sterility assurance.

• II.8.A pre-sterilisation bio-burden monitoring programme for the product and primary packaging material shall be developed to support parametric release. The monitoring shall be performed for each batch and the sampling locations of filled units before sterilisation shall be based on a worst-case scenario and be representative of the batch. Any organisms found shall be identified to confirm that they are not spore forming, which may be more resistant to the sterilising process.

• II.9.Appropriate measurement of critical process parameters during sterilisation is a critical requirement in a parametric release programme. The standards used for process measuring devices shall be specified and the calibration shall be traceable to national or international standards.

• II.10.Critical process parameters shall be established, defined and undergo periodic re-evaluation. The operating ranges shall be developed based on the sterilisation process, the process capability, the calibration tolerance limits and parameter criticality.

• II.11.Routine monitoring of the steriliser shall demonstrate that the validated conditions necessary to achieve the specified process is achieved in each cycle. Critical processes shall be specifically monitored during the sterilisation phase.

• II.12.A sterilisation record shall be kept which shall include all the critical process parameters. Sterilisation records shall be checked for compliance with the specifications by at least two independent systems. These systems may consist of two people or a validated computer system plus a person.

• II.13.Once parametric release has been approved as part of the marketing authorisation, decisions for release or rejection of a batch shall be based on the approved specifications and the review of critical process control data. Routine checks of the steriliser, changes, deviations, unplanned and routine planned maintenance activities shall be recorded, assessed and approved before releasing the products to the market. Non-compliance with the specification for parametric release may not be overruled by a sterility test.

[^E0001]: 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).

[^E0002]: For the purposes of this Annex, ‘restricted access barrier system’ means a system that provides an enclosed, but not fully sealed, environment meeting defined air quality conditions, and using a rigid-wall enclosure and integrated gloves to separate its interior from the surrounding cleanroom environment. The inner surfaces of the RABS are disinfected and decontaminated with a sporicidal agent. Operators use gloves, half suits, rapid transfer system/ports and other integrated transfer ports to perform manipulations or convey materials to the interior of the RABS. Depending on the design, doors are rarely opened, and only under strictly pre-defined conditions.

[^E0003]: For the purposes of this Annex, ‘critical zone’ means a space within the aseptic processing area in which product and critical surfaces are exposed to the environment.

[^E0004]: For the purposes of this Annex, ‘first air’ means filtered air that has not been interrupted prior to contacting the exposed product and product contact surfaces.

[^E0005]: For the purposes of this Annex, ‘unidirectional airflow’ means an airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area.

[^E0006]: For the purposes of this Annex, ‘personnel airlock’ means an area of increasing cleanliness used for entry of personnel (e.g. from the grade D area to the grade C area, or from the C area to the grade B area).

[^E0007]: For the purposes of this Annex, ‘material airlock’ means an area used for transfer of materials and equipment.

[^E0008]: For the purposes of this Annex, ‘turbulent airflow’ means air that is not unidirectional. Turbulent air in cleanrooms shall flush the cleanroom via mixed flow distribution and ensure maintenance of an acceptable air quality.

[^E0009]: For the purposes of this Annex, ‘unidirectional airflow unit’ means a cabinet supplied with filtered unidirectional airflow. The concept is interchangeable with ‘laminar airflow unit’.

[^E0010]: It is noted that qualification of cleanrooms is a different process than environmental monitoring.

[^E0015]: For the purposes of this Annex, ‘isokinetic sampling head’ means a sampling head designed to disturb the air as little as possible so that the same particles go into the nozzle as would have passed the area if the nozzle had not been there (i.e. the sampling condition in which the mean velocity of the air entering the sample probe inlet is nearly the same (± 20 percent) as the mean velocity of the airflow at that location).

[^E0016]: For the purposes of this Annex, ‘water system’ means a system for producing, storing and distributing water, usually compliant to a specific pharmacopeia grade (e.g. purified water and water for injection).

[^E0017]: For the purposes of this Annex, ‘dead leg’ means a length of a non-circulating pipe (where fluid may remain static) that is greater than 3 internal pipe diameters.

[^E0018]: For the purposes of this Annex, ‘sterilising grade filter’ means a filter that, when appropriately validated, is able to remove a defined microbial challenge from a fluid or gas producing a sterile effluent. Usually, such filters have a pore size equal or less than 0,22 μm.

[^E0019]: For the purposes of this Annex, ‘terminal sterilisation’ means the application of a lethal sterilising agent or conditions to a product in its final container to achieve a predetermined sterility assurance level of 10^–6 or below (e.g. the theoretical probability of there being a single viable microorganism present on or in a sterilised unit is equal to or less than 1 × 10^-6).

[^E0020]: For the purposes of this Annex ‘critical intervention’ means an intervention into the critical zone.

[^E0022]: For the purposes of this Annex, ‘inherent interventions’ means interventions that are an integral part of the aseptic process and required for either set-up, routine operation or monitoring (e.g. aseptic assembly, container replenishment, environmental sampling) and which are foreseen in relevant standard operating procedures/work instructions.

[^E0023]: For the purposes of this Annex, ‘critical surface’ means a surface that may come directly in contact with, or otherwise directly affect the sterility/absence of contamination of, a product or its containers or closures.

[^E0024]: For the purposes of this Annex, ‘grade A air supply’ means air that has passed through a filter qualified as capable of producing grade A total particle quality air, but where there is no requirement to perform continuous total particle monitoring or meet grade A viable monitoring limits.

[^E0025]: For the purposes of this Annex, ‘post-aseptic processing terminal heat treatment’ means a terminal moist heat process employed after aseptic processing which has been demonstrated to provide a sterility assurance level ≤ 10^-6 but where the requirements of steam sterilisation (for example, F0 ≥ 8 min) are not fulfilled. This may also be beneficial in the destruction of viruses that may not be removed through filtration.

[^E0026]: For the purposes of this Annex, ‘biological indicators’ means a population of microorganisms inoculated onto a suitable medium (e.g. solution, container or closure) and placed within a steriliser or load or room locations to determine the sterilisation or disinfection cycle efficacy of a physical or chemical process. The challenge microorganism shall be selected and validated based upon its resistance to the given process. Incoming lot D-value, microbiological count and purity define the quality of the biological indicator.

[^E0027]: For the purposes of this Annex, ‘D value’ means the value of a parameter of sterilisation (duration or absorbed dose) required to reduce the number of viable organisms to 10 percent of the original number.

[^E0028]: For the purposes of this Annex, ‘Z value’ means the temperature difference that leads to a 10-fold change in the D-value of the biological indicators.

[^E0029]: For the purposes of this Annex, ‘rapid transfer system/port’ means a system used for the transfer of items into RABS or isolators that minimises the risk to the critical zone. An example would be a rapid transfer container with an alpha/beta port.

[^E0030]: For the purposes of this Annex, ‘equilibration time’ means the time that elapses between the attainment of the sterilisation temperature at the refence measurement point and the attainment of the sterilisation temperature at all points within the load.

[^E0031]: For the purposes of this Annex, ‘F0 value’ means the lethality expressed in terms of the equivalent time in minutes at the reference temperature delivered by the process to the sterilisation load, with reference to micro-organisms possessing the relevant theoretical z-value.

[^E0032]: For the purposes of this Annex, ‘Fh value’ means the lethality expressed in terms of the equivalent time in minutes at the reference temperature delivered by the process to the sterilisation load, with reference to micro-organisms possessing the relevant theoretical z-value.

[^E0033]: For the purposes of this Annex, ‘bacterial retention testing’ means a test performed to validate that a filter can remove bacteria from a gas or liquid. The test is usually performed using a standard organism, such as Brevundimonas diminuta at a minimum concentration of 10⁷ Colony Forming Units/cm².

[^E0034]: For the purposes of this Annex, ‘Form-Fill-Seal’ means an automated filling process, typically used for terminally sterilised products, which constructs the primary container out of a continuous flat roll of packaging film while simultaneously filling the formed container with product and sealing the filled containers in a continuous process. Form-Fill-Seal processes may utilize a single web system (where a single flat roll of film is wrapped around itself to form a cavity), or a dual web system (where two flat rolls of film are brought together to form a cavity), often with the aid of vacuum moulds or pressurised gases. The formed cavity is filled, sealed and cut into sections. Films typically consist of a polymeric material, polymeric coated foil or other suitable material.

[^E0035]: For the purposes of this Annex, ‘Blow-Fill-Seal’ means a technology in which containers are formed from a thermoplastic granulate, filled with product, and then sealed in a continuous, integrated, automatic operation. The two most common types of Blow-Fill-Seal machines are the Shuttle type (with Parison cut) and the Rotary type (Closed Parison).

[^E0036]: For the purposes of this Annex, ‘parison’ means the tube of polymer extruded by the Blow-Fill-Seal machine from which containers are formed.

[^E0037]: For the purposes of this Annex, ‘lyophilisation’ means a physical-chemical drying process designed to remove solvents, by way of sublimation, from both aqueous and non-aqueous systems, primarily to achieve product or material stability. Lyophilisation is synonymous to the term freeze-drying.

[^E0038]: For the purposes of this Annex, ‘single use systems’ means systems in which product contact components are used only once to replace reusable equipment such as stainless-steel transfer lines or bulk containers.

[^E0039]: For the purposes of this Annex, ‘leachables’ means chemical entities that, under normal conditions of use or storage, migrate from the product contact surface of the process equipment or containers into the product or material being processed.

[^E0040]: For the purposes of this Annex, ‘extractables’ means chemical entities that migrate from the surface of the process equipment, when exposed to an appropriate solvent at extreme conditions, into the product or material being processed.

[^E0045]: For the purposes of this Annex, ‘aseptic process simulation’ means the simulation of the entire aseptic manufacturing process to verify whether the process is adequate to ensure sterility/prevent contamination during production. It includes all operations associated with routine manufacturing, such as equipment assembly, formulation, filling, lyophilisation and sealing process as necessary.

[^E0046]: For the purposes of this Annex, ‘local isolates’ means suitably representative microorganisms of the site that are frequently recovered through environmental monitoring within the classified zone/areas especially grade A and B areas, personnel monitoring or positive sterility test results.

[^E0047]: For the purposes of this Annex, ‘overkill sterilisation’ means a process that is sufficient to provide at least a 12 log10 reduction of microorganisms having a minimum D-value of 1 minute.

[^E0053]: Bacillus Calmette–Guérin (BCG) vaccine.

[^E0054]: Personnel entering a contained area where organisms have not been handled in open circuit operations in the previous twelve hours are not regarded as being at risk of contamination, unless the organism involved is a biological agent where the corresponding disease does not exist in the relevant country or geographical area, or where the corresponding disease is subject to prophylactic measures or an eradication programme undertaken in the relevant country or geographical area.

[^E0055]: For the purpose of this Annex, ‘exotic organism’ means a biological agent where the corresponding disease does not exist in a relevant country or geographical area, or where the disease is the subject of prophylactic measures or an eradication programme undertaken in the relevant country or geographical area.

[^E0056]: For the purposes of this Annex, ‘clean in place’ means a method, usually automated, used to clean the internal surfaces of equipment, piping, vessels, and associated fittings without disassembling them.

[^E0057]: For the purposes of this Annex, ‘steam in place’ means a method, usually automated, of sterilising the internal surfaces of equipment, piping, vessels, and associated fittings by using steam, without disassembling the equipment.

[^E0059]: For the purposes of this Annex, ‘specified pathogen free’ means animals free from specified pathogens. Such flocks or herds share a common environment and have their own caretakers who have no contact with non-specified pathogen free groups.

[^E0060]: For the purposes of this Annex, ‘master seed lot’ means a culture of a micro-organism distributed from a single bulk into containers and processed together in a single operation in such a manner as to ensure uniformity and stability and to prevent contamination.

For the purposes of this Annex, ‘working seed lot’ means a culture of a micro-organism derived from the master seed lot and intended for use in production.

[^E0061]: For the purposes of this Annex, ‘master cell bank’ means a culture of cells distributed into containers in a single operation, processed together and stored in such a manner as to ensure uniformity and stability and to prevent contamination.

For the purposes of this Annex, ‘working cell bank’ means a culture of cells derived from the master cell bank and intended for use in the preparation of production cell cultures. Genetically modified/genome edited working bank is used with the same meaning but for plants or animals that have been genetically modified or whose genome has been edited.

[^E0062]: For the purposes of this Annex, ‘clean/contained area’ means an area constructed and operated in such a manner that it achieves the aims of both a clean area and a contained area at the same time.

[^E0063]: Allergens that are chemically modified to reduce IgE reactivity.

[^E0064]: A low molecular weight molecule that is not in itself antigenic unless conjugated to a ‘carrier’ molecule.

[^E0068]: For the purposes of this Section, ‘cylinder’ means a container, usually cylindrical, suited for compressed, liquefied or dissolved gas, fitted with a device to regulate the spontaneous outflow of gas at atmospheric pressure and room temperature.

[^E0069]: For the purposes of this Section, ‘mobile cryogenic vessel’ means a mobile thermally insulated container designed to maintain the contents in a liquid state. This term does not include the tankers.

[^E0070]: For the purposes of this Section, ‘home cryogenic vessel’ means a mobile cryogenic vessel designed to hold liquid oxygen and dispense gaseous oxygen at patients’ home.

[^E0071]: For the purposes of this Section, ‘container’ means a cryogenic vessel (tank, tanker or other type of mobile cryogenic vessel) a cylinder, a cylinder bundle or any other package that is in direct contact with the gas.

[^E0072]: For the purposes of this Section, ‘manifold’ means equipment or apparatus designed to enable one or more gas containers to be emptied or filled at the same time.

[^E0073]: For the purposes of this Section, ‘tank’ means a static thermally insulated container designed for the storage of a liquefied or a cryogenic gas. A tank can also be called ‘fixed cryogenic vessel’.

[^E0074]: For the purposes of this Section, ‘tanker’ means a thermally insulated container fixed on a vehicle for the transport of a liquefied or a cryogenic gas.

[^E0075]: For the purposes of this Section, ‘purge’ means the removal of residual gas from a container/system by first pressurising and then venting the gas used for purging to 1.013 bar.

[^E0076]: For the purposes of this Section, ‘liquefied gas’ means a gas which, when packaged for transport, is partially liquid (or solid) at a temperature above – 50 ^oC.

[^E0077]: For the purposes of this Section, ‘non-return valve’ means a valve that permits flow in one direction only.

[^E0078]: For the purposes of this Section, ‘minimum pressure retention valve’ means a cylinder valve, which maintains a positive pressure above atmospheric pressure in a gas cylinder after use, in order to prevent internal contamination of the cylinder.

[^E0079]: For the purposes of this Section, ‘evacuation’ means the removal of a residual gas from a container/system to a pressure less than 1,013 bar, using a vacuum system.

[^E0080]: For compressed gases, a maximum theoretical impurity of 500 ppm v/v should be obtained for a filling pressure of 200 bar at 15 °C (and equivalent for other filling pressures).

[^E0081]: Note for Guidance CPMP/QWP/1719/00.

[^E0082]: For the purposes of this Annex, ‘IT infrastructure’ means the hardware and software that is necessary for the system to function (e.g. networking software and operation systems).

[^E0083]: Adequate process knowledge is particularly relevant where the concept of design space is used as well as for the development of any mathematical models.

[^E0084]: For the purposes of this Annex, ‘cleaning verification’ means the gathering of evidence through chemical analysis after each batch/campaign to show that the residues of the previous product or cleaning agents have been reduced below the scientifically set maximum limit.

[^E0085]: See EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

[^E0087]: Cross-reference to information provided in Appendix 1 or 2 is acceptable.

[^E0088]: For the purposes of this Annex, ‘continuous processing mode’ means a type of irradiation process where an automatic system conveys the products into the radiation cell, past the exposed radiation source along a defined path and at an appropriate speed, and out of the cell.

[^E0089]: For the purposes of this Annex, ‘batch mode’ means a type of irradiation process where the product is arranged at fixed locations around the radiation source and cannot be loaded or unloaded while the radiation source is exposed.

[^E0090]: The testing equipment is integrated into the process line, where the analysis is implemented under the process conditions. After the measurement, the sample moves forward continuously along the flow. This was the original method for real-time analysis.

[^E0091]: The sample is extracted from the process line in a statistically representative way and introduced to the measurement zone. The measurement conditions are similar to those of the process line. After the measurement, the sample may be drained as waste or introduced back to the process line.