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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

Type Implementing Regulation

Publication 2025-10-17

Last updated 2026-07-16

State In force

Department European Commission, SANTE

Source EUR-Lex

articles 46

Reform history JSON API

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 (Text with EEA relevance)

CHAPTER I

GENERAL PROVISIONS

Article 1

Subject matter and scope

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;

(d) liquids creams and ointments;

(e) medicinal gases;

(f) pressurised metered dose aerosol products for inhalation.

Article 2

Definitions

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

(1) ‘pharmaceutical quality system’ means the total sum of the measures implemented as part of the manufacturing process to ensure that medicinal products are of the quality required for their intended use;

(2) ‘quality risk management’ means a systematic process, applied both proactively and retrospectively, for the assessment, control, communication and review of risks to the quality of the veterinary medicinal product across the product’s lifecycle;

(3) ‘manufacturing site’ means a site that is engaged in any of the activities for which a manufacturing authorisation is required in accordance with Article 88(1) of Regulation (EU) 2019/6;

(4) ‘batch’ means a defined quantity of materials or product that undergo the same process(es) so that it can be expected to be homogeneous. For the control of the finished product, a batch of a veterinary medicinal product comprises all the units of a pharmaceutical form which are made from the same initial mass of materials and have undergone a single series of manufacturing operations or a single sterilisation operation or, in the case of a continuous production process, all the units manufactured in a given period of time. In the case of continuous manufacturing, a batch corresponds to a defined fraction of the production, characterised by its intended homogeneity;

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

(6) ‘intermediate product’ means a partly processed material which must undergo further manufacturing steps before it becomes a bulk product;

(7) ‘finished product’ means a veterinary medicinal product that has undergone all the stages of production, including packaging in its final container;

(8) ‘packaging’ means all operations, including filling (with the exception of sterile filling) and labelling, which a bulk product has to undergo in order to become a finished product;

(9) ‘packaging material’ means any material employed in the packaging of a veterinary medicinal product, excluding any outer packaging used for transportation or shipment. Packaging material can relate to immediate packaging or outer packaging;

(10) ‘in-process controls’ means the checks performed during production in order to monitor and, if necessary, adjust the process to ensure that the product conforms to the required specifications. Environmental monitoring and equipment controls are part of in-process controls;

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

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

(13) ‘reference sample’ means a sample of a batch of materials used in the manufacture of a veterinary medicinal product or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned;

(14) ‘retention sample’ means a sample of a fully packaged unit from a batch of finished product which is stored for identification purposes;

(15) ‘reprocessing’ means the treatment of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations;

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

(17) ‘clean area’ means an area designed, maintained, and controlled to prevent particle and microbiological contamination;

(18) ‘contained area’ means an area that is designed (including air handling and filtration), maintained and controlled so as to prevent contamination of the external environment by biological or other agents;

(19) ‘segregated area’ means an area within a manufacturing site that has separate storage, separate production suite with separate HVAC (heat, ventilation and air conditioning), dedicated equipment reserved solely for the production of one type of product with a specific risk profile and restrictions on the movement of personnel and equipment;

(20) ‘airlock’ means an enclosed space with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude ingress of particle matter and microorganism contamination from a lesser controlled area. A pass-through hatch has the same meaning as ‘airlock’ but is typically of a smaller size;

(21) ‘closed system’ means a system designed and operated so as to avoid exposure of the product or material to the room environment. Materials may be introduced to a closed system, but the addition must be done in such a way so as to avoid exposure of the product to the room environment (e.g. by means of sterile connectors or fusion systems). A closed system may need to be opened (e.g. to install a filter or make a connection) but it is returned to a closed state through a sanitisation or sterilisation step prior to process use;

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

(23) ‘isolator’ means an enclosure capable of being subject to reproducible interior bio-decontamination, with an internal work zone meeting grade A conditions that provides uncompromised, continuous isolation of its interior from the external environment (e.g. surrounding cleanroom air and personnel). There are two major types of isolators: (a) closed isolator systems, which exclude external contamination of the isolator’s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations; (b) open isolator systems, which are designed to allow for the continuous or semi-continuous ingress or egress of materials during operations through one or more openings. Openings are engineered (e.g. using continuous overpressure) to exclude the entry of external contaminant into the isolator;

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

(25) ‘aseptic processing/manufacturing’ means processing or manufacturing activities performed under conditions which prevent contamination;

(26) ‘quarantine’ means the isolation – physically or by other effective means – of materials, intermediate, bulk or finished products whilst awaiting a decision on their release or refusal;

(27) ‘reconciliation’ means a comparison, having due regard for normal variation, between the amount of product or materials theoretically and actually produced or used;

(28) ‘bracketing’ means an approach such that only the extremes of certain predetermined factors are tested or validated. The design assumes that validation of any intermediate levels is covered by the tests or validation of the extremes;

(29) ‘matrix’ means an approach where a subset of the total number of possible samples for all factor combinations is tested at a specified time point and another subset of samples is tested for all factor combinations at a subsequent time point. The results of each subset of samples is assumed to be representative for all samples at a given time point;

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

Article 3

Role of the marketing authorisation holder regarding good manufacturing practice

CHAPTER II

PHARMACEUTICAL QUALITY SYSTEM

Article 4

Implementation of a pharmaceutical quality system

Article 5

Requirements of the pharmaceutical quality system

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.

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

Product quality reviews

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;

(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.

Article 7

Self-inspection

Article 8

Management review

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.

CHAPTER III

PERSONNEL

Article 9

General requirements for personnel

Article 10

Training

Article 11

Hygiene

CHAPTER IV

PREMISES AND EQUIPMENT

Article 12

General requirements for premises

Article 13

Production areas

Article 14

Quality control areas

Article 15

Storage areas

Article 16

Ancillary areas

Article 17

Temperature and environmental controls

Article 18

Equipment

Article 19

Qualification of premises and equipment

CHAPTER V

DOCUMENTATION

Article 20

Documentation system

Article 21

Specifications and instructions

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.

Article 22

Records

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.

Article 23

Article 24

Retention periods

Article 25

Data integrity

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.

CHAPTER VI

PRODUCTION

Article 26

General requirements for production

Article 27

Handling of materials and products

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;

(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.

Article 28

Qualification of suppliers and compliance with specifications

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.

Article 29

Prevention of cross-contamination

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;

(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.

Article 30

Packaging operations

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

(a) general appearance of the packages;

(b) whether the packages are complete;

(d) whether any over-printing is correct;

(e) correct functioning of line monitors.

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

Article 31

Rejected, recovered and returned materials

Article 32

Use of ionising radiation

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

CHAPTER VII

QUALITY CONTROL

Article 33

General requirements for quality control

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;

(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;

(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;

(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.

Article 34

Sampling

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;

(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;

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

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

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.

Physical samples of packaging materials used in the re-packaging process, such as labels, carton, patient information leaflet or other package inserts, shall be retained for the duration of the shelf-life of the re-packaged finished product.

A retention sample of the re-packaged finished product shall:

(a) be taken for each re-packaging operation;

(b) be retained for at least one year after the expiry date of the re-packaged finished product;

(d) include the immediate packaging as well as the outer packaging.

By way of derogation from the third subparagraph, if the outer packaging of the veterinary medicinal product is not opened during the re-packaging process, only the outer packaging materials of the re-packaged finished product shall be retained in accordance with the second subparagraph.

A photographic/digital sample of the re-packaged finished product shall:

(a) allow a full visual examination of the re-packaged product that is equivalent to that of a physical retention sample;

(b) include all data on both the immediate and outer packaging, including the batch number and expiry date;

Article 35

Testing

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;

(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.

Article 36

On-going stability programme

Article 37

Technical transfer of testing methods

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;

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

(e) the acceptance criteria.

CHAPTER VIII

CERTIFICATION AND BATCH RELEASE

Article 38

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.

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

Certification and batch release

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;

(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.

Article 40

Additional considerations for imports of veterinary medicinal products

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.

Article 41

Repackaging operations

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.

Article 42

Handling of unplanned deviations

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.

CHAPTER IX

OUTSOURCED ACTIVITIES

Article 43

Requirements for outsourced activities

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.

CHAPTER X

QUALITY DEFECTS AND RECALL OF PRODUCTS

Article 44

Quality defects

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.

Article 45

Product recalls

CHAPTER XI

FINAL PROVISIONS

Article 46

Entry into force and application

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.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

ANNEX I

SECTION I

SCOPE

The additional requirements set out in this Annex shall apply to the manufacture of sterile products and products where aseptic manufacturing is required.

SECTION II

GENERAL PRINCIPLES

II.1.The manufacture of sterile products is subject to special requirements in order to minimise risks of microbial, particulate and endotoxin/pyrogen contamination. The following aspects shall be specifically considered:

(a) premises, equipment and processes shall be appropriately designed, qualified and/or validated and, where applicable, subjected to ongoing verification. The use of appropriate technologies (e.g. restricted access barriers systems, isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) shall be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, particulate and microbial contamination, and assist in the rapid detection of potential contaminants in the environment and in the product;

(b) personnel shall have adequate qualifications and experience and training with a specific focus on the principles involved in the protection of sterile products;

(c) processes and monitoring systems for the manufacture of sterile products shall be designed, commissioned, qualified, monitored and regularly reviewed by personnel with appropriate knowledge (including on aspects related to the process and relevant engineering and microbiological knowledge);

(d) raw materials and packaging materials shall be adequately controlled and tested to ensure that the level of bioburden and endotoxin/pyrogen are suitable for use;

(e) processes associated with the finishing and storage of sterile products shall not compromise the sterility of the product. Aspects to be considered in this regard include container integrity and maintenance of adequate storage conditions;

(f) all non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures shall be adequately investigated before certification/release of the batch. The investigation shall determine the potential impact on the process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation shall be clearly justified and recorded.

II.2.Processes, equipment, premises and manufacturing activities shall be managed in accordance with quality risk management principles so as to proactively identify, evaluate and control potential risks to quality. Monitoring or testing alone are not considered sufficient – on their own – to ensure sterility.

II.3.A contamination control strategy shall be developed by the manufacturer and be implemented in the site. The contamination control strategy shall aim at avoiding contamination by identifying all the critical control points and assessing the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures implemented to manage the risks. The effectiveness of the contamination control strategy shall be periodically reviewed and, where appropriate, updated and shall also drive continual improvement of the manufacturing and control methods.

II.4.While the contamination control strategy includes a series of interrelated measures that are typically assessed, controlled and monitored individually, the effectiveness of the implemented measures shall be assessed altogether.

II.5.The development of the contamination control strategy requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxin) as well as particulate (e.g. glass and other visible and sub-visible particles). Elements to be considered within a contamination control strategy include but are not limited to:

— plant and processes design, including the associated documentation;

— premises and equipment;

— personnel;

— utilities;

— raw material controls, including in-process controls;

— product containers and closures;

— approval of key component suppliers and critical service providers;

— management of outsourced activities and availability/transfer of critical information between parties;

— process validation, including validation of sterilisation processes;

— preventive maintenance: maintaining equipment, utilities and premises (planned and unplanned maintenance) so as to minimise the risk of contamination;

— cleaning and disinfection;

— monitoring systems, including an assessment of the feasibility of the introduction of scientifically sound, alternative methods that optimise the detection of environmental contamination;

— prevention mechanisms: trend analysis, detailed investigation, root cause determination, corrective and preventive actions and the need for comprehensive investigational tools;

— continuous improvement based on information derived from the above.

II.6.Changes to the systems in place shall be assessed for any impact on the contamination control strategy before and after implementation.

II.7.The manufacturer shall take all the steps and precautions necessary to ensure the sterility of the products manufactured within its facilities. Sole reliance shall not be placed on any terminal process or finished product test.

SECTION III

PREMISES

III.1. General requirements

III.1.1.The manufacture of sterile products shall be carried out in appropriate cleanrooms, entry to which shall be through change rooms that act as airlocks for personnel and airlocks for equipment and materials.

III.1.2.Cleanrooms and change rooms shall be maintained to an appropriate cleanliness standard and supplied with air that has passed through filters of an appropriate efficiency. Controls and monitoring shall be scientifically justified and shall effectively evaluate the state of environmental conditions of cleanrooms, airlocks and pass-through hatches.

III.1.3.The various operations of component preparation, product preparation and filling shall be carried out with appropriate technical and operational separation measures within the cleanroom or the premises to prevent mix up and contamination.

III.1.4.Restricted Access Barrier Systems (RABS) (²) or isolators can minimise microbial contamination associated with direct human interventions in the critical zone (³). Their use shall therefore be considered as part of the contamination control strategy; the use of alternative approaches shall be justified.

III.1.5.The following grades of cleanroom/zone shall be used:

(a) Grade A: for high-risk operations, such as aseptic processing line, filling zone, stopper bowl, open primary packaging or for making aseptic connections under the protection of first air (⁴). Grade A conditions are usually provided by a localised airflow protection, such as unidirectional airflow (⁵) workstations within RABS or isolators. The maintenance of unidirectional airflow shall be demonstrated and qualified across the whole of the grade A area. Direct intervention (e.g. without the protection of barrier and glove port technology) into the grade A area by operators shall be minimised.

(b) Grade B: this is the background cleanroom for grade A for aseptic preparation and filling (except for isolators). Air pressure differences shall be continuously monitored. Cleanrooms of lower grade than grade B may be considered where isolator technology is used (see Section III.3.3 of this Annex).

(c) Grade C and D: for less critical stages in the manufacture of aseptically filled sterile products or as a background for isolators. They may also be used for the preparation/filling of terminally sterilised products.

III.1.6.In cleanrooms and critical zones, all exposed surfaces shall be smooth, impervious and unbroken in order to minimise the shedding or accumulation of particles or micro-organisms.

III.1.7.To reduce the accumulation of dust and to facilitate cleaning there shall be no recesses that are difficult to clean effectively. Therefore, projecting ledges, shelves, cupboards and equipment shall be kept to a minimum. Doors shall be designed to avoid recesses that cannot be cleaned. Sliding doors are generally undesirable for this reason.

III.1.8.Materials used in cleanrooms, both in the construction of the room and for items used within the room, shall be selected to minimise generation of particles and to permit the repeated application of cleaning, disinfectant and sporicidal agents as appropriate.

III.1.9.Ceilings shall be designed and sealed to prevent contamination from the space above them.

III.1.10.Sinks and drains are not allowed in the grade A and grade B areas. In other grades, air breaks shall be fitted between the machine or sink and the drains. Floor drains in lower grade cleanrooms shall be fitted with traps or water seals designed to prevent back flow and shall be regularly cleaned, disinfected and maintained.

III.1.11.Cleanrooms shall be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and shall flush the area effectively. Adjacent rooms of different grades shall have an air pressure difference of a minimum of 10 Pascals (guidance value). Particular attention shall be paid to the protection of the critical zone.

III.1.12.The above-referred requirements regarding air supplies and pressures may be modified where necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or bacterial materials). The modification may include positively or negatively pressurised airlocks that prevent the hazardous material from contaminating the surrounding areas. Where for reasons of containment, it is necessary for the air to flow into a critical zone, the source of the air shall be from an area of the same or higher grade.

III.1.13.Decontamination of facilities (e.g. the cleanrooms and the heating, ventilation, and air-conditioning (HVAC) systems) and the treatment of air leaving a clean area, may be necessary for some operations based on a risk assessment (e.g. in the context of production involving pathogenic, highly toxic or radioactive materials or live viral or bacterial materials, when there is a risk of spreading to the environment, or when contamination has been detected).

III.1.14.Airflow patterns within cleanrooms and zones shall be visualised and it shall be demonstrated that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor), operators or equipment so that contamination may be transferred to the higher-grade areas. In particular, the following applies:

(a) Where unidirectional airflow is required, visualisation studies shall be performed to determine compliance.

(b) Where filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualisation studies shall demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area.

(c) Where air movement is shown to be a contamination risk to the clean area or critical zone, corrective actions, such as design improvement, shall be implemented.

(d) Airflow pattern studies shall be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns shall be retained. The outcome of the air visualisation studies shall be documented and be duly considered when establishing the facility’s environmental monitoring programme.

III.1.15.Indicators of air pressure differences shall be installed between cleanrooms and/or between isolators and their background. Set points and the criticality of air pressure differences shall be addressed as part of the contamination control strategy. Air pressure differences identified as critical shall be continuously monitored and recorded. A warning system shall be in place to instantly indicate and warn operators of any failure in the air supply or reduction of air pressure differences (below set limits for those identified as critical). The warning signal shall not be overridden without an assessment and a procedure shall be available to outline the steps to be taken when a warning signal is given. Where alarm delays are set, these shall be assessed and justified. Other air pressure differences shall be monitored and recorded at regular intervals.

III.1.16.Facilities shall be designed to permit observation of production activities from outside the grade A and B areas (e.g. through the provision of windows or remote cameras with a full view of the area and processes to allow observation and supervision without entry). This requirement shall be implemented when designing new facilities or during refurbishment of existing facilities.

III.2. Transfer of equipment and materials and movement of personnel

III.2.1.The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination and appropriate controls shall be therefore implemented. In particular, the transfer of materials, equipment, and components into the grade A or B areas shall be carried out via a unidirectional process. Where possible, items shall be sterilised and passed into these areas through double-ended sterilisers (e.g. through a double-door autoclave or a depyrogenation oven/tunnel) sealed into the wall. Where sterilisation upon transfer of the items is not possible, a validated procedure which achieves the same objective of not introducing contamination shall be implemented (e.g. using an effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter). The removal of items from the grade A and B areas (e.g. materials, waste, environmental samples) shall be carried out via a separate unidirectional process. If this is not possible, a time-based separation of movement (incoming/exiting material) shall be considered and adequate controls shall be applied to avoid potential contamination.

III.2.2.Only materials and equipment that have been included on an approved list, which is developed on the basis of an assessment during the validation of the transfer process, shall be transferred into the grade A or grade B areas via an airlock or pass-through hatches. Any unapproved items that require transfer shall be pre-approved as an exception.

III.2.3.The movement of material or equipment from a lower grade or unclassified area to a higher-grade clean area shall be subject to cleaning and disinfection commensurate with the risks. Equipment and materials (intended for use in the grade A area) shall be protected when transiting through the grade B area. Appropriate risk assessment and mitigation measures shall be applied and recorded, including a specific disinfection and monitoring programme approved by the department responsible for quality assurance.

III.2.4.Airlocks shall be designed and used to provide physical separation and to minimise microbial and particle contamination of the different areas and shall be used for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement shall be separated from those used for material movement. Where this is not possible, time-based separation of movement (personnel/material) shall be considered. Airlocks shall be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock shall, in the ‘at rest’ state, be of the same cleanliness grade (viable and total particle) as the cleanroom into which it leads. The use of separate change rooms for entering and leaving the grade B area is desirable. Where this is not possible, time-based separation of activities (ingress/egress) shall be considered. Where the risk of contamination is high, separate change rooms for entering and leaving production areas shall be used.

III.2.5.The following aspects shall be considered in the design of airlocks:

— Personnel airlocks (⁶): In general, hand-washing facilities shall be provided only in the first stage of the changing room and not be present in changing rooms directly accessing the grade B area.

— Material airlocks (⁷): Airlock and pass-through hatches shall be designed to protect the higher-grade environment, for example by effective flushing with an active filtered air supply.

For pass-through hatches and airlocks (for material and personnel), the entry and exit doors shall not be opened simultaneously. For airlocks leading to the grade A and grade B areas, an interlocking system shall be used. For airlocks leading to grade C and D areas, at least a visual and/or audible warning system shall be implemented. Where required to maintain the segregation of the area, a time delay between the closing and opening of interlocked doors shall be implemented.

III.3. Barrier technologies

III.3.1.Isolators and RABS and associated processes shall be designed to provide protection through the separation of the grade A environment from the environment of the surrounding room. The hazards introduced from the entry or removal of items during processing shall be minimised by the implementation of appropriate technologies or validated systems.

III.3.2.The design of the technology and processes used shall ensure that appropriate conditions are maintained in the critical zone to protect the exposed product during the operations.

(a) Requirements for isolators: — The design of open isolators shall ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from the exposed products during processing. — The design of closed isolators shall ensure grade A conditions with adequate protection for the exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow (⁸) shall not increase the risk of contamination of the exposed product. Where processing lines are included in closed isolators, grade A conditions shall be ensured with first air protection in the critical zone and unidirectional airflow that sweeps over and away from the exposed products during processing. — Negative pressure isolators shall only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialised risk control measures shall be applied to ensure that the critical zone is not compromised.

(b) Requirements for RABS: The design of RABS shall ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment shall be maintained.

III.3.3.The background environment for isolators or RABS shall ensure that the risk of transfer of contamination is minimised.

(a) Requirements for isolators: — The background classification applied shall be based on a risk assessment and justified as part of the contamination control strategy. The background environment for open isolators shall generally correspond to a minimum of grade C, while the background for closed isolators shall correspond to a minimum of grade D. — Key considerations when performing the risk assessment for the contamination control strategy of an isolator include the bio-decontamination programme, the extent of automation, the impact of glove manipulations that may potentially compromise ‘first air’ protection of the critical process points, the impact of potential loss of barrier/glove integrity, transfer mechanisms used and activities such as set-up or maintenance that may require the doors to be opened prior to the final bio-decontamination of the isolator. Where additional process risks are identified, a higher grade of background shall be implemented unless appropriately justified in the contamination control strategy. — Airflow pattern studies shall be performed at the interfaces of open isolators to demonstrate the absence of air ingress.

(b) Requirements for RABS: The background environment for RABS used for aseptic processing shall correspond to a minimum of grade B and airflow pattern studies shall be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.

III.3.4.The materials used for glove systems (for both isolators and RABS) shall have appropriate mechanical and chemical resistance. The frequency of glove replacement shall be defined as part of the contamination control strategy.

(a) Requirements for Isolators: — Leak testing of the glove system shall be performed using a suitable methodology having regard to the intended use and the risks involved. The testing shall be performed at defined intervals. In general, glove integrity testing shall be performed at least at the beginning and at the end of each batch or campaign. Additional glove integrity testing may be necessary depending on the campaign length. Glove integrity monitoring shall include a visual inspection associated with each use and following any manipulation that may affect the integrity of the system. For manual aseptic processing activities (i.e. the operator manually compounds, fills, places and/or seals an open container with sterile product) where a single unit or a small-size batch is produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session. — Integrity/leak testing of the isolator system shall be performed at defined intervals.

(b) Requirements for RABS: Gloves used in the grade A area shall be sterilised before installation and sterilised or effectively bio-decontaminated by a validated method prior to each manufacturing campaign. If during operation there is exposure to the background environment, there shall be disinfection using an approved methodology after each exposure. Gloves shall be visually examined with each use, and integrity testing shall be performed at periodic intervals.

III.3.5.Decontamination methods (cleaning and bio-decontamination, and – where applicable – inactivation for biological materials) shall be duly documented. The cleaning process prior to the bio-decontamination step is essential as any residues that remain may inhibit the effectiveness of the decontamination process. It shall be demonstrated that the cleaning and bio-decontamination agents used do not have an adverse impact on the product produced within the RABS or isolator.

(a) Requirements for isolators: The bio-decontamination process of the interior shall be automated, validated and controlled within defined cycle parameters and shall include a sporicidal agent in a suitable form (e.g. gaseous or vaporised form). Gloves shall be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) shall render the interior surfaces and critical zone of the isolator free from viable microorganisms.

(b) Requirements for RABS: The sporicidal disinfection shall include the routine application of a sporicidal agent using a method that has been validated and demonstrated to cover all areas of the interior surfaces and ensure a suitable environment for aseptic processing.

III.4. Cleanroom and clean air equipment qualification

III.4.1.Cleanrooms and clean air equipment such as unidirectional airflow units (⁹), RABS and isolators, used for the manufacture of sterile products/aseptic manufacturing, shall be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risk of contamination of the product or materials being handled. Appropriate cleanliness levels in the ‘at rest’ and ‘operational’ states shall also be maintained.

III.4.2.Cleanrooms and clean air equipment shall be qualified in accordance with Annex V. Through the qualification of cleanrooms and clean air equipment, the level of compliance of a classified cleanroom or clean air equipment with the relevant requirements having regard to the intended use is assessed (¹⁰). The following is part of the qualification requirements (where relevant to the design/operation of the installation):

— installed filter system leakage and integrity testing;

— airflow tests – volume and velocity;

— air pressure difference test;

— airflow direction test and visualisation;

— microbial airborne and surface contamination;

— temperature measurement test;

— relative humidity test;

— recovery test;

— containment leak test.

III.4.3.Cleanroom classification is part of the cleanroom qualification. Through the cleanroom classification the level of air cleanliness is assessed by measuring the total particle concentration. Classification activities shall be scheduled and performed so as to avoid any impact on process or product quality. For example, initial classification shall be performed during simulated operations and reclassification performed during simulated operations or during aseptic process simulation.

III.4.4.For cleanroom classification, the total amount of particles equal to or greater than 0,5 and 5 μm shall be measured. This measurement shall be performed both at rest and in simulated operations in accordance with the limits specified in Table 1:

— ‘at rest’ state is the condition whereby the installation of all the utilities is complete including any functioning HVAC, with the main manufacturing equipment installed as specified but not operating and without personnel present in the room.

— The total particle limits given in Table 1 for the ‘at rest’ state shall be achieved after a ‘clean up’ period on completion of operations and line clearance/cleaning activities. The ‘clean up’ period (guidance value of less than 20 minutes) shall be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation.

— ‘in operation’ state is the condition where the installation of the cleanroom is complete, the HVAC system fully operational, equipment installed and functioning in the manufacturer’s defined operating mode with the maximum number of personnel present performing or simulating routine operational work.

	Maximum limits for total particle ≥ 0,5 μm/m³	Maximum limits for total particle ≥ 5 μm/m³
Grade	at rest	in operation	at rest	in operation
A	3 520	3 520	Not specified (¹)	Not specified (¹)
B	3 520	352 000	Not specified (¹)	2 930
C	352 000	3 520 000	2 930	29 300
D	3 520 000	Not pre-defined (²)	29 300	Not pre-defined (²)
(¹) Classification including 5μm particles may be considered where relevant in accordance with the contamination control strategy or historical trends. (²) For grade D, in operation limits are not pre-defined. The manufacturer shall establish relevant in operation limits based on a risk assessment and routine data where applicable.

III.4.5.For classification of the cleanroom, the minimum number of sampling locations and their positioning as set out in ISO 14644 Part 1 shall be followed. For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations shall be considered as appropriate having regard to the risks, and all critical processing areas such as the point of fill and container closure feeder bowls shall be evaluated. Critical processing locations shall be determined on the basis of a documented risk assessment and knowledge of the process and operations to be performed in the area.

III.4.6.The speed of air supplied by unidirectional airflow systems shall be clearly justified in the qualification protocol including the location for air speed measurement. Air speed shall be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection for the product and open components at the working position (e.g. where high-risk operations occur and where product and/or components are exposed). Unidirectional airflow systems shall provide a homogeneous air speed in a range of 0,36–0,54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the contamination control strategy. Airflow visualisation studies shall correlate with the air speed measurement.

III.4.7.The microbial contamination level of the cleanrooms shall be determined as part of the cleanroom qualification. The number of sampling locations shall be based on a documented risk assessment and the results obtained from room classification, air visualisation studies and knowledge of the process and operations to be performed in the area. The maximum limits for microbial contamination during qualification for each grade are given in Table 2. Qualification shall include both ‘at rest’ and ‘in operation’ states.

Grade	Air sample CFU (²)/m³	Settle plates (diameter 90 mm) CFU/4 hours (²)	Contact plates (diameter 55 mm) CFU/plate
A	No growth
B	10	5	5
C	100	50	25
D	200	100	50
(¹) For the purposes of this Annex, ‘colony forming unit’ or ‘CFU’ means a single detectable colony that originates from one or more microorganisms. Colony forming units are typically expressed as CFU per ml for liquid samples, CFU per m³ for air sample and CFU per sample for samples captured on solid medium such as settle or contact plates. (²) Settle plates shall be exposed for the duration of operations and changed as required after a maximum of 4 hours. Exposure time shall be based on recovery studies and shall not allow desiccation of the media used. Note 1: All methods indicated for a specific grade in the table shall be used for qualifying the area of that specific grade. If one of the methods tabulated is not used, or alternative methods are used, the approach taken shall be appropriately justified. Note 2: Limits are applied using CFU throughout the document. If different or new technologies are used that present results in a manner different from CFU, the manufacturer shall scientifically justify the limits applied and where possible correlate them to CFU. Note 3: For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 shall apply. Note 4: Sampling methods shall not pose a risk of contamination to the manufacturing operations.

III.4.8.The requalification of cleanrooms and clean air equipment shall be carried out periodically following defined procedures. The requalification shall include at least the following:

— cleanroom classification (total particle concentration);

— integrity test of final filters;

— airflow volume measurement;

— verification of air pressure difference between rooms;

— air velocity test: this test is required for filling zones supplied with unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS). In the case of grade B, C and D areas, the conduct of the air velocity test shall be based on a risk assessment, which shall be documented as part of the contamination control strategy. Finally, for grades with non-unidirectional airflow, the air velocity test shall be replaced by a measurement of recovery testing.

III.4.9.The maximum time interval for requalification of grade A and B areas is 6 months, while for grade C and D areas the maximum time interval for requalification is 12 months.

In addition, appropriate requalification consisting of at least the above tests shall also be carried out following completion of a remedial action implemented to rectify an out of compliance in the equipment or premises or, as appropriate, after changes to equipment, premises or processes. Examples of changes requiring requalification include the interruption of air movement which affects the operation of the installation, a change in the design of the cleanroom or of the operational setting parameters of the HVAC system, or maintenance activities affecting the operation of the installation (e.g. change of final filters).

III.5. Disinfection

III.5.1.Particular attention shall be paid to the disinfection of cleanrooms. Specifically, cleanrooms shall be cleaned and disinfected thoroughly in accordance with a written programme. More than one type of disinfecting agent shall be used to ensure that, where they have different modes of action, their combined usage is effective against bacteria and fungi. Disinfection shall include the periodic use of a sporicidal agent. Monitoring to assess the effectiveness of the disinfection programme and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use) shall be undertaken regularly.

For disinfection to be effective, it is necessary to previously clean to remove surface contamination. Additionally, in some cases, a cleaning process shall be implemented to effectively remove disinfectant residues.

III.5.2.The disinfection process shall be validated. Validation studies shall demonstrate the suitability and effectiveness of the disinfectants in the specific manner in which they are used and on the type of surface material, or representative material if justified, and shall support the in-use expiry periods of prepared solutions.

III.5.3.Disinfectants and detergents used in grade A and grade B areas shall be sterile prior to use. Disinfectants used in grade C and D may also have to be sterile when this is considered appropriate in the contamination control strategy. Where the disinfectants and detergents are diluted/prepared by the sterile product manufacturer, this shall be done in a manner to prevent contamination and there shall be monitoring for microbial contamination. Dilutions shall be kept in previously cleaned containers (and sterilised where applicable) and shall only be stored for the relevant defined period. If the disinfectants and detergents are supplied ‘ready-made’, the results from certificates of analysis or conformance may be accepted subject to successful completion of the appropriate vendor qualification.

III.5.4.Where fumigation or vapour disinfection (e.g. Vapour-phase Hydrogen Peroxide) of cleanrooms and associated surfaces are used, the effectiveness of the fumigation agent and of the dispersion system used shall be understood and validated.

SECTION IV

EQUIPMENT

IV.1.A written, detailed description of the equipment shall be available (including process and instrumentation diagrams as appropriate). This shall form part of the initial qualification package and shall be kept up to date.

IV.2Equipment monitoring requirements shall be established as part of the qualification. Process and equipment alarm events shall be acknowledged and evaluated for trends. The frequency at which alarms are assessed shall be based on their criticality (critical alarms shall be reviewed immediately).

IV.3.As far as possible, equipment, fittings and services shall be designed and installed so that operations, maintenance and repairs can be performed outside the cleanroom. If maintenance has to be performed in the cleanroom and the required standards of cleanliness and/or asepsis cannot be maintained, precautions such as restricting access to the work area to specified personnel or the generation of clearly defined work protocols and maintenance procedures shall be considered. Additional cleaning, disinfection and environmental monitoring shall also be considered. If sterilisation of equipment is required, it shall be carried out, wherever possible, after complete reassembly.

IV.4.The cleaning process shall be validated as being able to remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used, and to minimise the chemical, microbial and particulate contamination of the product during the process and prior to disinfection.

IV.5.For aseptic processes, direct and indirect product contact parts shall be sterilised. For the purpose of complying with this requirement, ‘direct product contact parts’ are those parts of the equipment that the product passes through, such as filling needles or pump, while ‘indirect product contact parts’ are those parts of the equipment that are not in contact with the product but may come into contact with other sterilised surfaces that are critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components).

IV.6.All equipment such as sterilisers, air handling systems (including air filtration) and water systems shall be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return to use shall be approved.

IV.7.Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an assessment of the potential impact to the sterility of the product shall be performed and recorded.

IV.8.A conveyor belt shall not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in a sterilising tunnel).

IV.9.Particle counters, including sampling tubing, shall be qualified. The manufacturer’s recommended specifications shall be considered for tube diameter and bend radii. Tube length shall typically be no longer than 1 m unless justified and the number of bends shall be minimised. Portable particle counters with a short length of sample tubing shall be used for classification purposes. Isokinetic sampling heads (¹¹) shall be used in unidirectional airflow systems. They shall be oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative.

SECTION V

UTILITIES

V.1. General requirements

V.1.1.The nature and extent of controls applied to utility systems shall be commensurate with the risk to the quality of the product associated with the utility. The impact of the utility on the quality of the product is to be determined via a risk assessment and documented as part of the contamination control strategy.

The following utilities can generally be considered associated with a higher risk:

— utilities that are in direct contact with the product, e.g. water for washing and rinsing, gases and steam for sterilisation;

— contact materials that will ultimately become part of the product;

— contact surfaces that come into contact with the product;

— utilities that otherwise directly impact the product.

V.1.2.Utilities shall be designed, installed, qualified, operated, maintained and monitored in a manner that ensures that the utility system functions as expected.

V.1.3.Results for critical parameters and critical quality attributes of high-risk utilities shall be subject to regular trend analysis to ensure that the system capabilities remain appropriate.

V.1.4.Records of the utility system installation shall be kept throughout the utility system’s life-cycle, including drawings and schematic diagrams, construction materials and system specifications. Important information that shall be kept includes:

— pipeline flow direction, slopes, diameter and length;

— tank and vessel details;

— valves, filters, drains, sampling and user points.

V.1.5.Pipes, ducts and other utilities shall not be present in cleanrooms. If unavoidable, then they shall be installed so that they do not create recesses, unsealed openings or surfaces that are difficult to clean. In addition, the installation shall allow the cleaning and disinfection of the outer surface of the pipes.

V.2. Water systems (¹²)

V.2.1.Water treatment plants and distribution systems shall be designed, constructed, installed, commissioned, qualified, monitored and maintained so as to prevent microbiological contamination and ensure a reliable source of water of an appropriate quality. In particular, measures shall be taken to minimise the risk of presence of particulates, microbial contamination/proliferation and endotoxin/pyrogen (e.g. sloping of piping to provide complete drainage and the avoidance of dead legs (¹³)). Where filters are included in the system, special attention shall be paid to their monitoring and maintenance.

V.2.2.Water systems shall be qualified and validated to maintain the appropriate levels of physical, chemical and microbial control, taking the effect of seasonal variations into account.

V.2.3.Water flow shall remain turbulent through the pipes in water distribution systems to minimise the risk of microbial adhesion, and subsequent biofilm formation. The flow rate shall be established during the qualification and be routinely monitored.

V.2.4.Water for injections shall be produced from water that meets the specifications defined during the qualification process and it shall be stored and distributed in a manner that minimises the risk of microbial growth (e.g. by constant circulation at a temperature above 70 °C). Moreover, water for injections shall be produced by distillation or by a purification process that is equivalent to distillation, such as reverse osmosis coupled with other appropriate techniques such as electrodeionisation (EDI), ultrafiltration or nanofiltration.

V.2.5.Where water for injection storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters shall not be a source of contamination and the integrity of the filter shall be tested before installation and after use. Controls shall be put in place to prevent condensation formation on the filter (e.g. by heating).

V.2.6.To minimise the risk of biofilm formation, sterilisation, disinfection or regeneration of water systems shall be carried out according to a predetermined schedule and also as a remedial action following out-of-limit or specification results. When chemicals are used to disinfect a water system, a validated rinsing/flushing procedure shall be subsequently performed. Additionally, water shall be tested after disinfection/regeneration. Chemical testing results shall be checked before the water system is returned to use and it shall be verified that microbiological/endotoxin results are within specification before batches manufactured using water from the system are considered for certification/release.

V.2.7.Regular ongoing chemical and microbial monitoring of water systems shall be performed to ensure that the water continues to meet compendial requirements. Alert levels shall be set on the basis of the initial qualification data and thereafter be periodically reassessed on the basis of data obtained during subsequent re-qualifications, routine monitoring and investigations. Review of ongoing monitoring data shall be carried out to identify any adverse trend in the performance of the system. Sampling programmes shall be based on the qualification data and shall consider the potential worst case sampling locations ensuring that at least one representative sample of the water that is used for manufacturing processes is included every day as well as any other additional requirement that may be necessary in accordance with the contamination control strategy. To ensure that representative water samples are obtained for analysis on a regular basis, sampling programmes shall address all outlets and points of use at a specified interval.

V.2.8.Alert level excursions shall be documented and reviewed and include an investigation to determine whether the excursion is a single (isolated) event or if the results are indicative of an adverse trend or of the deterioration of the system. Each action limit excursion shall be investigated to determine the probable root cause(s) and any potential impact on the product quality and manufacturing processes.

V.2.9.Water for injection systems shall include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations shall be based on risk.

V.2.10.Water used in production shall comply with the current monograph of the relevant Pharmacopeia.

V.3. Steam used as a direct sterilising agent

V.3.1.Feed water to a pure steam (clean steam) generator shall be appropriately purified. Pure steam generators shall be designed, qualified and operated in a manner to ensure that the quality of the steam produced meets the defined chemical and endotoxin levels.

V.3.2.Steam used as a direct sterilising agent shall be of a suitable quality and shall not contain additives at a level that could cause contamination to the product or the equipment. In the case of generators supplying pure steam for the direct sterilisation of materials or product-contact surfaces (e.g. porous hard-good autoclave loads), the steam condensate shall meet the requirements of the current monograph for water for injections of the relevant Pharmacopeia (microbial testing is not mandatory for steam condensate). A suitable sampling schedule shall also be in place to ensure that representative pure steam is obtained for analysis on a regular basis. Other aspects of the quality of the pure steam used for sterilisation shall be assessed periodically against validated parameters, including – unless otherwise justified – non-condensable gases, dryness value (dryness fraction) and superheat.

V.4. Gases and vacuum systems

V.4.1.Gases that come in direct contact with the product or primary container surfaces shall be of appropriate chemical, particulate and microbial quality. All relevant parameters, including oil and water content, shall be specified taking into account the use and type of the gas, the design of the gas generation system and, where applicable, comply with the current monograph of the relevant Pharmacopeia or the product quality requirement.

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