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

— certification statement by the qualified person, date and signature.

V.6.   Production

V.6.1.Transfers and deliveries of cryogenic and liquefied gas (⁶⁰) shall be done in accordance with the following requirements:

(a) The transfer of cryogenic or liquefied gases from primary storage, including the controls before the transfer, shall be in accordance with validated procedures designed to avoid the possibility of contamination. Transfer lines shall be equipped with non-return valves (⁶¹) or other suitable alternatives. Flexible connections, coupling hoses and connectors shall be flushed with the relevant gas before use.

(b) The transfer hoses used to fill tanks and tankers shall be equipped with product-specific connections. The use of adaptors allowing the connection of tanks and tankers not dedicated to the same gases shall be adequately controlled.

(c) Deliveries of gas may be added to tanks containing the same defined quality of gas provided that a sample is tested to ensure that the quality of the delivered gas is acceptable. That sample may be taken from the gas to be delivered or from the receiving tank after delivery.

(d) The filling of tanks retained by customers at customer’s premises is to be done according to Section V.7.3.

V.6.2.Filling and labelling of cylinders and mobile cryogenic vessels shall be done in accordance with the following requirements:

(a) Before filling cylinders and mobile cryogenic vessels, a batch (batches) of gas(es) shall be determined, controlled according to specifications and approved for filling.

(b) In the case of continuous processes, adequate in-process controls shall be implemented to ensure that the gas complies with the specifications.

(c) Cylinders, mobile cryogenic vessels and valves shall conform to appropriate technical specifications and relevant requirements of the marketing authorisation. They shall be dedicated to a single medicinal gas or to a given mixture of medicinal gases. Cylinders shall be colour-coded according to relevant standards. They shall preferably be fitted with minimum pressure retention valves (⁶²) with non-return mechanism in order to provide adequate protection against contamination.

(d) Cylinders, mobile cryogenic vessels and valves shall be checked before first use in production and shall be properly maintained. Where CE marked medical devices are used, the maintenance shall be in accordance with the manufacturer’s instructions.

(e) Checks and maintenance operations shall not affect the quality and the safety of the medicinal product. The water used for the hydrostatic pressure testing carried out on cylinders shall be at least of drinking quality.

(f) As part of the checks and maintenance operations, cylinders shall be subject to an internal visual inspection before fitting the valve, to make sure that they are not contaminated with water or other contaminants. Specifically, this is required when they are new and initially put into medicinal gas service, following any hydrostatic statutory pressure test or equivalent test where the valve is removed, or whenever the valve is replaced.

(g) After fitting, the valve shall be kept closed to prevent any contamination from entering the cylinder. If there is any doubt about the internal condition of the cylinder, the valve shall be removed and the cylinder internally inspected to ensure that it has not been contaminated.

(h) Maintenance and repair operations of cylinders, mobile cryogenic vessels and valves are the responsibility of the manufacturer of the medicinal product. If subcontracted, they shall only be carried out by approved subcontractors, and contracts – including technical specifications – shall be established. Subcontractors shall be audited to ensure that appropriate standards are maintained.

(i) A system to ensure the traceability of cylinders, mobile cryogenic vessels and valves shall be put in place.

(j) Checks to be performed before filling include: — For cylinders, a check according to a defined procedure shall be carried out to ensure there is a positive residual pressure in each cylinder. If the cylinder is fitted with a minimum pressure retention valve and there is no signal indicating that there is a positive residual pressure, the correct functioning of the valve shall be checked. If the valve is shown not to function properly, the cylinder shall be sent to maintenance. If the cylinder is not fitted with a minimum pressure retention valve and there is no positive residual pressure, the cylinder shall be put aside for additional measures, to make sure that it is not contaminated with water or other contaminants; additional measures such as of internal visual inspection followed by cleaning using a validated method may be considered. — A check to ensure that all previous batch labels have been removed. — A check to verify that any damaged product labels have been removed and replaced. — A visual external inspection of each cylinder, mobile cryogenic vessel and valve for dents, arc burns, debris, other damage and contamination with oil or grease; cleaning shall be done if necessary. — A check of each cylinder or mobile cryogenic vessel outlet connection to determine that it is the proper type for the particular gas involved. — A check of the date of the next test to be performed on the valve (in the case of valves that need to be periodically tested). — A check of the cylinders or mobile cryogenic vessels to ensure that any tests required by national or international regulations (e.g. hydrostatic pressure test or equivalent for cylinders) have been conducted and are still valid. — A check to determine that each cylinder is colour-coded as specified in the marketing authorisation (colour-coding of the relevant national/international standards).

(k) Cylinders that have been returned for refilling shall be prepared with care in order to minimise the risks of contamination, in line with the procedures defined in the marketing authorisation. These procedures, which shall include evacuation (⁶³) and/or purging operations, shall be validated (⁶⁴).

(l) Mobile cryogenic vessels that have been returned for refilling shall be prepared with care in order to minimise the risks of contamination, in line with the procedures defined in the marketing authorisation. In particular, mobile vessels with no residual pressure shall be prepared using a validated method.

(m) There shall be appropriate checks to ensure that each cylinder/mobile cryogenic vessel has been properly filled.

(n) Each filled cylinder shall be tested for leaks using an appropriate method, prior to fitting the tamper evident seal. The test method shall not introduce any contaminant into the valve outlet and, where applicable, shall be performed after any quality sample is taken.

(o) After filling, cylinders valves shall be fitted with covers to protect the outlets from contamination. Cylinders and mobile cryogenic vessels shall be fitted with tamper-evident seals.

(p) Each cylinder or mobile cryogenic vessel shall be labelled. The batch number and the expiry date may be on a separate label.

(q) In the case of medicinal gases produced by mixing two or more different gases (in-line before filling or directly into the cylinders), the mixing process shall be validated to ensure that the gases are properly mixed in every cylinder and that the mixture is homogeneous.

V.7.   Quality control

V.7.1.For cylinders, the sampling plan and the analysis to be performed shall meet, the following requirements, unless stated otherwise in the marketing authorisation:

(a) In the case of a single medicinal gas filled into cylinders via a multi-cylinder manifold, the gas from at least one cylinder from each manifold filling cycle shall be tested for identity and assay each time the cylinders are changed on the manifold.

(b) In the case of a single medicinal gas filled into cylinders one at a time, the gas from at least one cylinder of each uninterrupted filling cycle shall be tested for identity and assay. An example of an uninterrupted filling cycle is one shift's production using the same personnel, equipment and batch of gas to be filled.

(c) In the case of a medicinal gas produced by mixing two or more gases in a cylinder from the same manifold, the gas from every cylinder shall be tested for assay and identity of each component gas. For excipients, if any, testing on identity may be performed on one cylinder per manifold filling cycle (or per uninterrupted filling cycle in case of cylinders filled one at a time). It is acceptable to test fewer cylinders in case of validated automated filling system.

(d) Premixed gases shall follow the same principles as single gases when continuous in-line testing of the mixture to be filled is performed. Premixed gases shall follow the same principle as medicinal gases produced by mixing gases in the cylinders when there is no continuous in-line testing of the mixture to be filled.

Testing for water content shall be performed unless otherwise justified.

V.7.2.Final testing on mobile cryogenic vessels shall include a test for assay and identity on each vessel, unless otherwise stated in the marketing authorisation. Testing by batches is only acceptable if it has been demonstrated that the critical attributes of the gas remaining in each vessel before refilling have been maintained.

V.7.3.Cryogenic vessels retained by customers (tanks in healthcare facilities or home cryogenic vessels) which are refilled in place from dedicated tankers do not need to be sampled after filling provided that a certificate of analysis on the contents of the tanker accompanies the delivery. However, it shall be demonstrated that the specification of the gas in the vessels is maintained over the successive refillings.

V.7.4.Reference and retention samples are not required, unless otherwise specified. On-going stability studies are not required in case initial stability studies have been replaced by bibliographic data (⁶⁵).

VI.   PRESSURISED METERED DOSE AEROSOL PREPARATIONS FOR INHALATION

VI.1.   General

VI.1.1.The manufacture of pressurised metered dose aerosol veterinary medicinal products for inhalation with metering valves shall be done under conditions which minimise microbial and particulate contamination.

VI.1.2.Assurance of the quality of the valve components and, in the case of suspensions, of uniformity is particularly important.

VI.2.   Premises and equipment

VI.2.1.Whenever possible, manufacture and filling shall be carried out in a closed system.

VI.2.2.Where products or clean components are exposed, the area shall be fed with filtered air, comply with the requirements of at least a Grade D environment and be entered through airlocks.

VI.3.   Production and quality control

VI.3.1.The specifications, sampling and testing for the metering valves shall adequately address the complexity thereof.

VI.3.2.The valve manufacturer shall be audited as regards compliance with quality requirements.

VI.3.3.All fluids (e.g. liquid or gaseous propellants) shall be filtered to remove particles greater than 0,2 micron. An additional filtration immediately before filling shall be considered, where possible.

VI.3.4.Containers and valves shall be cleaned using a validated procedure appropriate to the use of the product to ensure the absence of any contaminants such as processing aids (e.g. lubricants) or undue microbiological contaminants. After cleaning, valves shall be kept in clean, closed containers and precautions shall be taken not to introduce contamination during subsequent handling, e.g. taking samples. Containers shall be fed to the filling line in a clean condition or cleaned on-line immediately before filling.

VI.3.5.Precautions shall be taken to ensure uniformity of suspensions at the point of fill throughout the filling process.

VI.3.6.When a two-shot filling process is used, it is necessary to ensure that both shots are of the correct weight in order to achieve the correct composition. For this purpose, 100 % weight checking at each stage is recommended.

VI.3.7.Controls after filling shall ensure the absence of undue leakage. Any leakage test shall be performed in a way that avoids microbial contamination or residual moisture.

ANNEX IV

I. SCOPE

The requirements set out in this Annex shall apply to computerised systems that are used in connection with the manufacture of veterinary medicinal products, in so far as such use falls under the scope of good manufacturing practices. The use of computer systems in manufacturing sites for purposes not connected with the pharmaceutical quality system (e.g. staff matters, commercial issues, etc.) are not concerned by the requirements in this Annex.

II.   GENERAL REQUIREMENTS

II.1.IT infrastructure (⁶⁶) used in the manufacture of veterinary medicinal products shall be qualified. Any related software application shall also be validated. The extent of the validation shall be based on risk management principles having regard to the need to ensure product quality and data integrity.

II.2.The outsourcing of tasks/operations related to the installation, configuration, validation, maintenance, modification of a computerised system or any other related service or for data processing shall be made by means of a written contract that shall provide for a clear delineation of the responsibilities of each party.

II.3.The suitability of the contractor (including by means of audits where appropriate) shall be assessed applying risk management principles.

II.4.Documentation supplied with commercial off-the-shelf products shall be reviewed by the manufacturer to check that user requirements are fulfilled.

II.5.Suppliers of software specifically developed/adapted for use within the manufacturing process shall be qualified. Where necessary and upon the request of inspectors, the manufacturer of veterinary medicinal products shall be able to produce information from the quality system of the suppliers or developers of such specific software. The contractual agreements between the software suppliers and the manufacturer of veterinary medicinal products shall contain adequate provisions to this effect.

III.   DEVELOPMENT PHASE

III.1.The manufacturer shall take all reasonable steps to ensure that the system is suitable to ensure the quality of the product, the consistency of the manufacturing process and compliance with the goals of the pharmaceutical quality system.

III.2.User requirements specifications shall describe the required functions of the computerised system and shall be based on risk assessment principles. User requirement specifications shall be traceable throughout the life-cycle of the computerised system.

III.3.The standards, protocols, acceptance criteria, procedures and records shall be justified on the basis of a risk assessment.

III.4.The validation documentation and reports shall cover the relevant steps of the entire life cycle. The validation documentation shall include change control records (if applicable) and reports on any deviations observed during the validation process.

III.5.A process shall be in place for the validation of bespoke or customised computerised systems which ensures the formal assessment and reporting of the quality and performance parameters for all the life-cycle stages of the system.

III.6.The suitability of the testing procedures and test scenarios shall be demonstrated. System (process) parameter limits, data limits and error handling shall be duly considered. When automated testing tools are used, an assessment of their adequacy, including of the environment where the test is conducted, shall be required.

III.7.When data are transferred to another data format or system, it shall be verified that the migration process has not altered the data (in value or meaning).

IV.   OPERATIONAL PHASE

IV.1.An up-to-date listing of all the relevant systems and their functionality (inventory) shall be kept. In the case of critical systems, the system description shall detail the physical and logical arrangements, data flows and interfaces with other systems or processes, any hardware and software pre-requisites and security measures.

IV.2.Computerised systems exchanging data electronically with other systems shall include appropriate built-in checks for the correct and secure entry and processing of data.

IV.3.For critical data entered manually, an additional check on the accuracy of the data shall be performed. This check may be done by a second operator or by validated electronic means. The criticality and the potential consequences of erroneous or incorrectly entered data shall be addressed under risk management principles.

IV.4.Data shall be secured by both physical and electronic means against damage. The readability and accuracy of stored data shall be ensured, as well as the accessibility thereof throughout the retention period.

IV.5.Regular back-ups of all relevant data shall be done. Integrity and accuracy of backup data and the ability to restore the data shall be checked during validation and be periodically monitored.

IV.6.It shall be ensured that electronically stored data can be printed. For records supporting the batch release it shall be possible to generate printouts indicating if any of the data has been changed since the original entry.

IV.7.Based on a risk assessment, it may be appropriate to build into the system the creation of a record of all changes that are relevant to demonstrate compliance with good manufacturing practice and deletions (a system generated "audit trail"). In case of change or deletion of relevant data, the reason shall be documented. Audit trails shall be available and convertible to a generally intelligible form and regularly reviewed.

IV.8.Changes to a computerised system, including system configurations, shall only be made in a controlled manner in accordance with a defined procedure.

IV.9.Computerised systems shall be periodically evaluated to confirm that they remain in a valid state and in compliance with the requirements set out in this Annex. Such evaluations shall include, where appropriate, the current range of functionality, deviation records, incidents, problems, upgrade history, performance, reliability, security and validation status reports.

IV.10.Physical or logical controls shall be in place to restrict the access to computerised systems and the data storage area to authorised persons only. Suitable methods of preventing unauthorised entry to the system, commensurate to the criticality of the computerised system, shall be implemented.

IV.11.The generation, change or cancellation of access authorisations shall be recorded.

IV.12.The identity of operators creating, changing, confirming or deleting data shall be recorded, including the date and time where the operations occur.

IV.13.All incidents, not only system failures and data errors, shall be reported and assessed. The root cause of a critical incident shall be identified and shall form the basis for the implementation of corrective and preventive actions as appropriate.

IV.14.Electronic records may be signed electronically. Electronic signatures shall be permanently linked to their respective record and shall include the time and date when they were generated.

IV.15.When a computerised system is used for recording certification, the system shall be designed/controlled to ensure that only the Qualified Person can certify the batches.

IV.16.The continuity of operations performed by computerised systems supporting critical processes, shall be ensured in the event of a system breakdown (e.g. by means of a manual or another alternative system). The time required to bring the alternative arrangements into use shall be commensurate to the risks. The implemented arrangements shall be documented and tested.

IV.17.Data may be archived. This data shall be checked for accessibility, readability and integrity. If relevant changes are to be made to the system (e.g. computer equipment or programs), then the ability to retrieve the data shall be ensured and tested.

ANNEX V

I. SCOPE

The requirements set out in this Annex shall apply to the qualification of equipment, facilities, utilities and systems used for the manufacture of veterinary medicinal products and the validation of the manufacturing process. Computerised systems used for the manufacture of veterinary medicinal products shall be validated according to the requirements set out in Annex IV.

II.   GENERAL REQUIREMENTS

II.1.Decisions on the scope and extent of the qualification/validation shall be based on a documented risk assessment. Retrospective qualification/validation is not acceptable. Data supporting qualification/validation studies that were obtained from sources outside of the manufacturers own programmes may be used provided that this approach is justified and that there is adequate assurance of the reliability thereof to support the intended qualification/validation.

II.2.Qualification and validation activities shall take into consideration the life cycle of the relevant equipment, facilities, utilities, systems and of the veterinary medicinal product.

II.3.Any planned changes to the equipment, facilities, utilities, systems or manufacturing process that may affect the quality of the veterinary medicinal product shall be formally documented and its impact on the validated status or control strategy shall be assessed.

II.4.Qualification and validation activities shall only be performed by suitably trained personnel who follow approved procedures, including on reporting. There shall be appropriate oversight over the whole validation life cycle.

II.5.The key elements of the site qualification and validation programme shall be clearly defined and documented in a validation master plan or in an equivalent document, which – as a minimum – shall include or refer to the following:

(a) the general qualification and validation approach applied by the manufacturer;

(b) the organisational structure, including roles and responsibilities for qualification and validation activities;

(c) a summary of the equipment, facilities, utilities, systems, manufacturing processes on site and their qualification/validation status;

(d) the strategy for the implementation of changes (‘change control’) and management of deviations for qualification and validation;

(e) guidance on developing acceptance criteria;

(f) references to documents supporting/recording qualification and validation;

(g) the qualification and validation strategy/plan for the equipment, facilities, utilities, systems or processes, including requalification, where applicable.

II.6.A quality risk management approach shall be used for qualification and validation activities. Where required, in light of increased knowledge acquired during the life-cycle, the risk assessments shall be repeated. The way in which risk assessments are used to support qualification and validation activities shall be documented.

II.7.Appropriate checks shall be incorporated into qualification and validation work to ensure the integrity of all data obtained.

III.   DOCUMENTATION

III.1.All documents generated during qualification and validation shall be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system.

III.2.The inter-relationship between documents in complex qualification/validation projects shall be clearly defined.

III.3.Qualification/validation protocols defining the critical systems, attributes and parameters and the associated acceptance criteria shall be prepared.

III.4.Qualification documents may be combined together, where appropriate, e.g. installation qualification and operational qualification.

III.5.Where qualification/validation protocols and other documentation are supplied by a third party providing validation services, appropriate personnel at the manufacturing site shall confirm their suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use.

III.6.Any significant changes to the approved protocol during execution (e.g. acceptance criteria, operating parameters, etc.) shall be documented as a deviation and be scientifically justified.

III.7.Results that fail to meet the pre-defined acceptance criteria shall be recorded as a deviation and be fully investigated. Implications for the qualification/validation status shall be discussed in the report.

III.8.The review and conclusions of the qualification/validation shall be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria shall be scientifically justified and a final recommendation made as to the outcome of the qualification/validation.

III.9.A formal release for the next stage in the qualification/validation process shall be authorised by the relevant responsible personnel either as part of the qualification/validation report approval or as a separate summary document. Conditional approval to proceed to the next qualification/validation stage may be given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment supporting that there is no significant impact on the next activity.

IV.   QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS

IV.1.Qualification activities shall consider all stages, from the initial development of the user requirements specification up to the end use of the equipment, facility, utility or system. While the specific stages/criteria are to be adapted to the specific project characteristics, the main stages and some criteria that may be included in each stage are indicated in Sections IV.2 to IV.7 for orientation purposes.

IV.2.   User requirements specification

Specifications for equipment, facilities, utilities or systems shall be defined in a user requirements specification or a functional specification document. The essential elements of quality shall be built in at this stage and any risks mitigated to an acceptable level. The user requirement specification is a point of reference throughout the validation life cycle.

IV.3.   Design qualification

Design qualification is the documented verification that the proposed design of the equipment, facilities, utilities or systems is suitable for the intended purpose. Through design qualification the compliance of the design with good manufacturing practice shall also be demonstrated and documented. The requirements of the user requirements specification shall be verified during the design qualification.

IV.4.   Factory acceptance testing / Site acceptance testing

Where applicable, equipment may be evaluated at the vendor site, prior to delivery. This may be particularly relevant in case of novel or complex technologies.

Prior to installation, the equipment shall be confirmed to comply with the user requirements specification / functional specification at the vendor site, if applicable.

Where appropriate and justified, documentation review and some tests may be performed as part of the factory acceptance testing or other stages without the need for repetition thereof on site as part of installation qualification or operational qualification, provided that it is shown that the functionality is not affected by the transport and installation.

Factory acceptance testing may be supplemented by the execution of a site acceptance testing following the receipt of equipment at the manufacturing site.

IV.5.   Installation qualification (IQ)

Installation qualification is the documented verification that the equipment, facilities, utilities or systems, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Installation qualification shall include, but is not limited to the following:

(a) verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications;

(b) verification of the correct installation against the pre-defined criteria;

(c) collection and collation of supplier operating and working instructions and maintenance requirements;

(d) calibration of instruments;

(e) verification of the materials of construction.

IV.6.   Operational qualification (OQ)

Operational qualification is the documented verification that the equipment, facilities, utilities or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. While operational qualification usually follows installation qualification, depending on the complexity of the equipment, a combined installation/operation qualification may be performed.

Operational qualification shall include, but is not limited to, the following:

— tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed;

— tests to confirm upper and lower operating limits, including worst case conditions.

IV.7.   Performance qualification

Performance qualification is the documented verification that equipment, facilities, utilities or systems can perform effectively and reproducibly based on the approved specifications and manufacturing process. While this step shall generally take place after the successful completion of installation and operational qualification, in some cases, it may be appropriate to perform it in conjunction with operational qualification or process validation.

Performance qualification shall include tests, using production materials, qualified substitutes or a simulated product that has been demonstrated to have an equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control shall be justified.

Tests shall cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.

IV.8.The quality of steam, water, air and other gases shall be confirmed after the installation in accordance with the approach above-referred. The period and extent of the qualification shall take due consideration of seasonal variations (where relevant) and the intended use of the utility.

IV.9.A risk assessment shall be carried out in cases where there may be a direct contact with the product (e.g. heating, ventilation and air-conditioning (HVAC) systems) or an indirect contact (e.g. through heat exchangers) to mitigate any risks of failure.

IV.10.The qualification of the equipment used for primary packaging shall be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure.

V. RE-QUALIFICATION

V.1.Equipment, facilities, utilities and systems shall be re-evaluated at an appropriate frequency to confirm that they remain suitable for the intended operations.

V.2.The need for re-qualification (e.g. following changes to equipment/systems) shall be evaluated on the basis of quality risk management principles.

VI.   PROCESS VALIDATION

VI.1.   General requirements

VI.1.1.Process validation is the documented evidence that the process, operated within the established parameters, can perform effectively and reproducibly to produce a veterinary medicinal product within the required specifications and quality attributes and in compliance with the terms of the marketing authorisation.

VI.1.2.Through the process validation it shall be shown that all quality attributes and process parameters that are important for ensuring the required product quality can be consistently met by the process. The classification of process parameters and quality attributes as critical or non-critical shall be conducted having regard to available product and process knowledge (⁶⁷) and based on a risk assessment; it shall be duly documented.

VI.1.3.Manufacturing processes shall be shown to be capable of ensuring consistent production of a product of the required quality and in compliance with the requirements set in the marketing authorisation before the veterinary medicinal products are placed on the market. Retrospective validation is not acceptable.

VI.1.4.Process validation of new products shall cover all intended marketed strengths and sites of manufacture. Bracketing may be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme.

VI.1.5.For process validation of products that are transferred from one site to another or within the same site, the number of validation batches may be reduced by the use of a bracketing approach. This approach shall be scientifically justified on the basis of existing product knowledge. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified.

VI.1.6.Batches used for process validation shall usually be of the same size as the intended commercial scale batches; the use of any other batch sizes shall be duly justified.

VI.1.7.Equipment, facilities, utilities and systems used for process validation shall be qualified. In addition, test methods used for process validation shall be validated for their intended use.

VI.1.8.Validation batches may be released to the market only if this is pre-defined and provided that they comply with good manufacturing practice (including the validation acceptance criteria or continuous process verification criteria) and with the terms of the marketing authorisation.

VI.2.   Traditional process validation

VI.2.1.Under the so-called traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility.

VI.2.2.While it is generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions can constitute a validation of the process, the number of batches used for process validation shall be justified on the basis of a risk assessment that takes into consideration the complexity of the process and the variability of the results from the process as well as other relevant factors.

An alternative number of batches may be justified taking into account whether standard methods of manufacture are used and whether similar products or processes are already manufactured/used at the site. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an on-going process verification exercise.

VI.2.3.A process validation protocol shall be developed which shall define the critical process parameters (i.e. process parameters the variability of which have an impact on critical quality attributes and which therefore shall be monitored or controlled to ensure the desired product quality), critical quality attributes (i.e. physical, chemical, biological or microbiological characteristics that shall be controlled to ensure the desired product quality) and the associated acceptance criteria based on development data or process knowledge.

VI.2.4.Process validation protocols shall include, but are not limited to, the following:

(a) a short description of the process and a reference to the respective batch record;

(b) functions and responsibilities;

(c) a summary of the critical quality attributes to be investigated;

(d) a summary of critical process parameters and their associated limits;

(e) a summary of other (non-critical) attributes and parameters to be investigated or monitored during the validation activity, and the reasons for their inclusion;

(f) a list of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status;

(g) a list of analytical methods and method validation, as appropriate;

(h) proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected;

(i) additional testing to be carried out with acceptance criteria;

(j) the sampling plan and the rationale behind it;

(k) methods for recording and evaluating results;

(l) the process for release and certification of batches (if applicable).

VI.3.   Continuous process verification

VI.3.1.Continuous process verification may be used as an alternative to traditional process validation for products developed under a quality by design approach, where it has been scientifically established during the development phase that the established control strategy provides a high degree of assurance of product quality.

VI.3.2.The method by which the process will be verified shall be defined. There shall be a science-based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters. The control strategy shall be regularly evaluated. Process analytical technology and multivariate statistical process control may be used as tools.

VI.3.3.The number of batches necessary to demonstrate that the process is capable of consistently delivering a product of the desired quality and in compliance with the terms of the marketing authorisation shall be set case by case having regard to the specificities of the product and applying quality risk management principles.

VI.4.   Hybrid approach

VI.4.1.A hybrid of the traditional approach and continuous process verification may be used where there is a substantial amount of product and process knowledge gained from manufacturing experience and historical batch data.

VI.4.2.This approach may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach.

VI.5.   Ongoing process verification during lifecycle

VI.5.1.Ongoing process verification (also known as continued process verification) is the documented evidence that the manufacturing process is capable of ensuring consistent production of a product of the required quality and in compliance with the requirements set in the marketing authorisation. Ongoing process verification is applicable regardless of the approach to process validation implemented (traditional, continuous or hybrid).

VI.5.2.The extent and frequency of the ongoing process verification shall be reviewed periodically having regard to the level of process understanding and process performance.

VI.5.3.Ongoing process verification shall be conducted under an approved protocol or equivalent documents and a report shall be prepared to document the results obtained. Statistical tools shall be used, where appropriate, to support any conclusions.

VI.5.4.Ongoing process verification shall be used throughout the product lifecycle to support the validated status of the product, taking into consideration the outcome of the product quality review. Incremental changes over time shall also be considered and the need for any additional actions, e.g. enhanced sampling, shall be assessed.

VI.6.   Concurrent validation

VI.6.1.In exceptional circumstances, where there is a strong benefit-risk ratio for the treated animal, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation may be used. However, the decision to carry out concurrent validation must be justified, documented and approved by authorised personnel.

VI.6.2.Where a concurrent validation approach has been adopted, there shall be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusions shall be formally documented and available to the qualified person prior to the certification of the batch.

VII.   VALIDATION OF TEST METHODS

VII.1.Analytical methods that are used for the manufacture or control of veterinary medicinal products (including those supporting validation and qualification) shall be validated. The validation shall demonstrate the suitability of the analytical methods for the intended purpose.

VII.2.Analytical procedures, which are either described in the European Pharmacopoeia, the pharmacopoeia of a Member State, or are linked to a product specific monograph, and are performed according to the monograph, are generally considered as validated. In such cases, the suitability of the validated test for the intended purpose shall be verified.

VII.3.Where microbial testing of product is carried out, the method shall be validated to confirm that the product does not influence the recovery of microorganisms.

VII.4.Where microbial testing of surfaces in clean rooms is carried out, the test method shall be validated to confirm that the use of sanitising agents does not influence the recovery of microorganisms.

VIII.   CLEANING VALIDATION

VIII.1.Cleaning validation is the documented evidence that a given cleaning procedure reproducibly removes contaminants, residues from previous product and cleaning agents below a pre-defined threshold. Cleaning validation is required to confirm the effectiveness of cleaning procedures for all product contact equipment.

VIII.2.Simulating agents (i.e. materials that closely resemble the specific characteristics of the relevant product) may be used provided that it is scientifically justified.

VIII.3.The cleaning validation for similar types of equipment may be grouped together provided that it is duly justified.

VIII.4.While a visual check for cleanliness is part of the acceptance criteria for cleaning validation, this criterion alone is generally not sufficient. Moreover, repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach.

VIII.5.It is recognised that cleaning validation may take some time to complete and that, in such cases, verification (⁶⁸) after each batch is required until the validation is complete. When this approach is implemented, there shall be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use.

VIII.6.Validation shall consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment shall be validated.

VIII.7.An assessment shall be performed to determine the variable factors that influence the effectiveness and performance of the cleaning procedure (e.g. operators, the level of detail in procedures such as rinsing times, etc.) If variable factors have been identified, the worst case situations shall be used as the basis for the cleaning validation studies.

VIII.8.Limits for the carryover of product residues shall be based on a toxicological evaluation (⁶⁹), The justification for the selected limits shall be documented in a risk assessment including all the supporting references. Limits shall also be established for the removal of the cleaning agents used. Acceptance criteria shall consider the potential cumulative effect of multiple items of equipment used. The following adaptations are however possible:

(a) therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances;

(b) if it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity.

VIII.9.The risk presented by microbial and endotoxin contamination shall be considered during the development of cleaning validation protocols.

VIII.10.The influence of the time between the manufacture and the cleaning, and the time between the cleaning and the use shall be taken into account to define dirty and clean hold times for the cleaning process.

VIII.11.Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign shall be considered and the maximum length of a campaign (in time and/or number of batches) shall be the basis for cleaning validation exercises.

VIII.12.Where a worst-case product approach is used as a cleaning validation model, a scientific rationale shall be provided for the selection of the worst-case product and the impact of new products assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency.

VIII.13.Cleaning validation protocols shall specify or make reference to the locations to be sampled and the rationale for the selection of these locations and shall define the acceptance criteria.

VIII.14.Sampling may be carried out by swabbing, rinsing or by other means depending on the production equipment. The sampling materials and method applied shall not influence the result. Recovery shall be shown to be possible from all product contact materials sampled in the equipment with the sampling methods used.

VIII.15.The cleaning procedure shall be performed an appropriate number of times based on a risk assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.

VIII.16.Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated equipment or other appropriate measures shall be implemented.

VIII.17.Where manual cleaning of equipment is performed, the effectiveness of the manual process shall be confirmed at a justified frequency.

ANNEX VI

Note 1: The site master file relates to the pharmaceutical activities carried out at a specific site. If only part of a manufacturing process is undertaken at a site, the site master file need only relate to such operations (e.g. analysis, packaging).

Note 2: The site master file shall contain adequate information but, as far as possible, shall not exceed 25-30 pages, plus appendices. The document shall be readable when printed on A4 paper sheets.

Note 3: The site master file shall be kept up to date and be representative of current activities. The site master file shall have an edition number, the date when it becomes effective and the date by which it has to be reviewed. Each Appendix may have an individual effective date and be subject to a specific review date.

1. GENERAL INFORMATION ON THE MANUFACTURER

1.1.   Contact information on the manufacturer

— Name and official address of the manufacturer.

— Name and street address of the site, buildings and production units located on the site.

— Contact information of the manufacturer, including the telephone number of the personnel to be contacted in the case of product defects or recalls (this number shall be always operational, including outside business hours).

— Identification number of the site, using a geolocalisation system such as Galileo or GPS. In addition, OMS (⁷⁰) is mandatory for submissions in the EEA.

1.2.   Authorised pharmaceutical manufacturing activities of the site

— Copy of a valid manufacturing authorisation issued by the relevant competent authority shall be provided as Appendix 1. Alternatively, reference to the EudraGMDP database may be provided (where applicable). In cases where the relevant competent authority has not issued a manufacturing authorisation, this shall be explained.

— Brief description of the manufacture, control, storage, import, export, transport or other activities authorised by the relevant competent authority(ies), including foreign authorities, with reference to the authorised pharmaceutical forms/activities, respectively, where not covered by the manufacturing authorisation.

— A list with the type of products currently manufactured on-site shall be provided as Appendix 2, where not covered by Appendix 1 or EudraGMDP entry.

— List of GMP inspections of the site within the last 5 years, including dates and name/country of the Competent Authority having performed the inspection.

— A copy of the current GMP certificate or, alternatively, reference to the EudraGMDP database shall be provided as Appendix 3.

1.3.   Any other manufacturing activities carried out on the site

— Description of non-pharmaceutical activities on-site, if any.

2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER

2.1.   The quality management system of the manufacturer

— Brief description of the quality management systems run by the company and reference to the standards used.

— Responsibilities related to the maintenance of the quality system, including for senior management.

— Information about the activities for which the site is accredited and certified, including dates and contents of accreditations and names of the accrediting bodies.

2.2.   Release procedure of finished products

— Detailed description of the qualification requirements (education and work experience) of the authorised person(s) / qualified person(s) responsible for batch certification and releasing procedures.

— General description of batch certification and releasing procedure.

— Brief description of the batch release process, including the specific tasks of the authorised person / qualified person and arrangements for ensuring compliance with the marketing authorisation (where applicable).

— The arrangements between the authorised persons / qualified persons when several authorised persons / qualified persons are involved.

— Statement on whether the control strategy employs process analytical technology (PAT) or real time release or parametric release.

2.3.   Management of suppliers and contractors

— A brief summary of the supply chain and the external audit programme.

— Brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients and other suppliers of critical materials.

— Measures to ensure that products manufactured are compliant with TSE (transmissible spongiform encephalopathy) guidelines, where applicable.

— Measures to address instances when counterfeit/falsified products, bulk products (i.e. unpacked tablets), active pharmaceutical ingredients or excipients are suspected or identified.

— Use of outside scientific, analytical or other technical assistance in relation to the manufacture or control activities.

— List of contract manufacturers and laboratories, including addresses and relevant contact information, and flow charts of supply-chains for outsourced manufacturing and quality control activities (e.g. sterilisation of primary packaging material for aseptic processes, testing of starting raw materials, etc.) shall be provided as Appendix 4.

— Brief overview of the allocation of responsibilities between the contract giver and contract acceptor with respect to compliance with the marketing authorisation (where not included under 2.2).

2.4.   Quality Risk Management

— Brief description of the quality risk management methodologies used by the manufacturer.

— Scope and focus of the quality risk management, including a brief description of any activities which are performed at corporate level and those which are performed locally. Any application of the quality risk management system to avoid disruptions of supply linked to manufacturing issues shall be mentioned.

2.5.   Product Quality Reviews

— Brief description of the methodologies used.

3. PERSONNEL

— An organisation chart showing the arrangements for quality management, production and quality control positions/titles shall be provided as Appendix 5, including senior management and qualified person(s).

— Number of employees involved in the quality management, production, quality control and storage respectively.

4. PREMISES AND EQUIPMENT

4.1.   Premises

— Short description of the plant, including the size of the site and list of buildings. If production for different countries takes place in different buildings on the site, the buildings shall be listed with destined markets identified (if not identified under 1.1).

— Simple plan or description of the manufacturing areas with indication of the scale (architectural or engineering drawings are not required).

— Layouts and flow charts of the production areas shall be provided as Appendix 6, showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms.

— Layouts of warehouses and storage areas shall be provided as part of Appendix 6, with indication of special areas for the storage and handling of highly toxic, hazardous and sensitising materials, if applicable.

— Brief description of specific storage conditions if applicable, unless they are already indicated on the layouts.

4.1.1.Brief description of heating, ventilation and air conditioning (HVAC) systems:

— Principles for defining the air supply, temperature, humidity, pressure differentials and air change rates, policy of air recirculation (%).

4.1.2.Brief description of the water systems:

— Quality references of the water produced.

— Schematic drawings of the systems shall be provided as Appendix 7.

4.1.3.Brief description of other relevant utilities, such as steam, compressed air, nitrogen, etc.

4.2.   Equipment

4.2.1.Listing of major production and control laboratory equipment with critical pieces of equipment identified shall be provided as Appendix 8.

4.2.2.Cleaning and sanitation:

— Brief description of the cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic clean-in-place, etc.).

4.2.3.GMP critical computerised systems:

— Description of GMP critical computerised systems (excluding equipment specific programmable logic controllers).

5. DOCUMENTATION

— Brief description of the documentation system (i.e. electronic, manual).

— Where applicable, a list of the type of documents/records stored or archived off-site (including pharmacovigilance data, when applicable) shall be provided, as well as the name and address of storage site and an estimate of time required for retrieving documents from the off-site archive.

6. PRODUCTION

6.1.   Type of products (⁷¹)

— Type of products manufactured including a list of pharmaceutical forms.

— Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitising properties).

— Product types manufactured in a dedicated facility or on a campaign basis, if applicable.

— Process analytical technology (PAT) used, if applicable: general statement of the relevant technology and associated computerised systems.

6.2.   Process validation

— Brief description of the general policy for process validation.

— Brief description of the policy for reprocessing or reworking.

6.3.   Material management and warehousing

— Brief description of the arrangements for the handling of materials used in the production, including packaging materials, bulk and finished products. Sampling, quarantine, release and storage shall also be addressed.

— Brief description of the arrangements for the handling of rejected materials and products.

7. QUALITY CONTROL (QC)

— Brief description of the quality control activities carried out on the site in terms of physical, chemical, and microbiological and biological testing.

8. TRANSPORT, COMPLAINTS, PRODUCT DEFECTS AND RECALLS

8.1.   Transport arrangements (as applicable to the role of the manufacturer)

— Types (wholesale licence holders, manufacturing licence holders, etc.) and locations (EU/EEA, USA, etc.) of the companies to which the products are shipped from the site.

— Description of the system used to verify that each customer/recipient is legally entitled to receive the products from the manufacturer.

— Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/control.

— Arrangements for product distribution and methods by which product traceability is maintained.

— Measures taken to prevent manufacturers’ products to fall in the illegal supply chain.

8.2.   Complaints, product defects and recalls

— Brief description of the system for handling complaints, product defects and recalls.

9. SELF INSPECTIONS

— Brief description of the self-inspection system with a focus on the criteria used for the selection of the areas to be covered during planned inspections, practical arrangements and follow-up activities.

Appendices

— Appendix 1: Copy of valid manufacturing authorisation.

— Appendix 2: List of pharmaceutical forms manufactured including the INN-names or common name (as available) of the active pharmaceutical ingredients (API) used.

— Appendix 3: Copy of a valid GMP certificate.

— Appendix 4: List of contract manufacturers and laboratories including the addresses and contact information, and flow-charts of the supply chains for these outsourced activities.

— Appendix 5: Organisational charts.

— Appendix 6: Layouts of production areas, including material and personnel flows and general flow charts of manufacturing processes of each product type (pharmaceutical form), and layouts of warehouse and storage areas.

— Appendix 7: Schematic drawings of water systems.

— Appendix 8: List of major production and laboratory equipment.

ANNEX VII

I. GENERAL

The requirements set out in this Annex shall apply to the use of ionising radiation in the manufacture of veterinary medicinal products. The specific requirements set forth in this Annex shall apply only to the ionising radiation process, other aspects of the manufacturing process shall comply with the requirements set forth in this Regulation as appropriate.

The required radiation dose to be applied, including relevant limits, shall be provided for in the marketing authorisation.

II.   PREMISES

Premises shall be designed and operated to segregate irradiated from non-irradiated containers to avoid their cross-contamination. Where materials are handled within closed irradiation containers, it may not be necessary to segregate materials intended for use in the production of medicinal products from other type of materials, provided that there is no risk of the former being contaminated by the latter. Any possibility of contamination of the products by radionuclide from the source shall be excluded.

III.   EQUIPMENT

III.1.   Dosimeters

III.1.1.Dosimeters used shall be calibrated according to relevant standards. The period of validity of the calibration shall be documented in written with appropriate justification and be adhered to.

III.1.2.The same instrument shall normally be used to establish the calibration curve of the dosimeters and to measure the change in their absorbance after irradiation. If a different instrument is used, the absolute absorbance of each instrument shall be established.

III.1.3.Depending on the type of dosimeter used, due account shall be taken of possible causes of inaccuracy, including a change in moisture content, a change in temperature, the time elapsed between the irradiation and the measurement or the dose rate.

III.1.4.The wavelength of the instrument used to measure the change in absorbance of dosimeters and the instrument used to measure their thickness shall be subject to regular checks of calibration at intervals established having regard to the stability, purpose and usage.

III.2.   Irradiators

III.2.1.1.It shall be demonstrated, through appropriate documentation, that irradiators are able to perform consistently within predetermined limits when operated according to the process specifications. In this context, predetermined limits are the maximum and minimum doses designed to be absorbed by the irradiation container. It shall not be possible for variations to occur in the operation of the irradiator which give a dose to the container outside those limits without the knowledge of the operator.

III.2.1.2.When there is a change to the process or the irradiator that could affect the dose distribution to the irradiation container (e.g. change of source pencils), it shall be re-assessed whether the irradiator continues to consistently perform within the predetermined limits. The extent of the assessment needed depends on the extent of the change in the irradiator or the load that has taken place.

The irradiator shall be designed taking into account that the absorbed dose received by a particular part of an irradiation container at any specific point in the irradiator can be impacted by the following factors:

— the activity and geometry of the source;

— the distance from the source to the container;

— the duration of the irradiation controlled by the timer setting or conveyor speed;

— the composition and density of the material, including other products, between the source and the particular part of the container;

— the path of containers through a continuous irradiator or the loading pattern in a batch irradiator;

— the number of exposure cycles.

The results of the dose mapping procedure shall give minimum and maximum absorbed doses in the product and on the container surface for a given set of irradiator parameters, product density and loading pattern.

For the dose mapping procedure, the following elements shall apply:

(a) The irradiator shall be filled with irradiation containers packed with dummy products or a representative product of uniform density. Dosimeters shall be placed throughout a minimum of three loaded irradiation containers which are passed through the irradiator, surrounded by similar containers or dummy products. If the product is not uniformly packed, dosimeters shall be placed in a larger number of containers.

(b) The positioning of the dosimeters shall depend on the size of the irradiation container. For example, for containers up to 1 × 1 × 0,5 m, a three-dimensional 20 cm grid throughout the container including the outside surfaces might be suitable. If the expected positions of the minimum and maximum dose are known from a previous irradiator performance characterisation, some dosimeters could be removed from regions of average dose and replaced to form a 10 cm grid in the regions of extreme dose.

(c) Ideally, reference dosimeters shall be used because of their greater precision. Routine dosimeters are permissible but it is advisable to place reference dosimeters beside them at the expected positions of minimum and maximum dose and at the routine monitoring position in each of the replicate irradiation containers. The observed values of dose will have an associated random uncertainty that can be estimated from the variations in replicate measurements.

(d) The minimum observed dose, as measured by the routine dosimeters, necessary to ensure that all irradiation containers receive the minimum required dose shall be set having regard to the random variability of the routine dosimeters used.

(e) Irradiator parameters shall be kept constant, monitored and recorded during dose mapping. The records, together with the dosimetry results and all other records generated, shall be retained.

The irradiator shall be designed taking into account that the absorbed dose received by a particular portion of an irradiated product at any specific point in the irradiator can be impacted by the following factors:

— the characteristics of the beam, which are: electron energy, average beam current, scan width and scan uniformity;

— the conveyor speed;

— the product composition and density;

— the composition, density and thickness of material between the output window and the particular portion of product;

— the output window to container distance.

The results of the dose mapping procedure shall give minimum and maximum absorbed doses in the product and on the container surface for a given set of irradiator parameters, product density and loading pattern.

For the dose mapping procedure, dosimeters shall be placed between layers of homogeneous absorber sheets making up a dummy product, or between layers of representative products of uniform density, such that at least ten measurements can be made within the maximum range of the electrons. Requirements set forth in points (b) to (d) of Section III.2.2.2 shall apply also.

IV.   DOCUMENTATION

IV.1.The numbers of containers received, irradiated and dispatched shall be reconciled with each other and with the associated documentation. Any discrepancy shall be reported and resolved.

IV.2.The irradiator operator shall certify in writing the range of doses received by each irradiated container within a batch or delivery.

IV.3.Process and control records for each irradiation batch shall be checked and signed by a nominated responsible person and retained.

IV.4.The documentation associated with the validation/qualification of the irradiator shall be retained for one year after the expiry date or at least five years after the release of the last product processed by the irradiator, whichever is longer.

V. PROCESSING

V.1.   General

V.1.1.Irradiation containers shall be packed in accordance with the specified loading pattern(s) established during validation.

V.1.2.During the process, the radiation dose to the irradiation containers shall be monitored using validated dosimetry procedures. The relationship between that dose and the dose absorbed by the product inside the container must have been established during process validation and as part of the qualification of the irradiator.

V.1.3.Radiation indicators shall be used as an aid to differentiate irradiated from non-irradiated containers. However, they shall neither be used as the sole means of differentiation nor be considered as an indication of satisfactory processing.

V.1.4.Processing of mixed loads of containers within the irradiation cell shall only be done when there is evidence supporting that the radiation dose received by individual containers remains within the limits specified.

V.1.5.When the required radiation dose is – by design – achieved during more than one exposure or passage, this shall be specified as part of the contract, including relevant details regarding the predetermined time period. Unplanned interruptions during irradiation that extend the irradiation process beyond the specifications set forth in the contract shall be notified to the contract giver, who shall bring the information to the attention of the qualified person.

V.1.6.Non-irradiated products shall be segregated from irradiated products at all times. Methods of achieving this objective include the use of radiation indicators and appropriate design of premises.

V.2.   Gamma irradiators

V.2.1.For continuous processing modes (⁷²), the following shall apply:

(a) dosimeters shall be placed so that at least two are exposed in the irradiation at all times;

(b) there shall be a positive indication of the correct position of the source and an interlock between source position and conveyor movement. The conveyor speed shall be monitored continuously and recorded.

V.2.2.For batch modes (⁷³), the following shall apply:

(a) at least two dosimeters shall be exposed in positions related to the minimum dose position;

(b) source movement and exposure times for each batch shall be monitored and recorded.

V.2.3.For a given desired dose, the timer setting or conveyor speed shall be adjusted for source decay and source additions. The period of validity of the setting or speed shall be recorded and adhered to.

V.3.   Electron beam irradiators

V.3.1.A dosimeter shall be placed on every container.

V.3.2.There shall be continuous recording of average beam current, electron energy, scan-width and conveyor speed. These variables, other than conveyor speed, shall be controlled within the pre-defined limits established pursuant to Section III.2.1.

VI.   PROCESS VALIDATION

VI.1.Through process validation it shall be demonstrated that the delivery of the intended absorbed dose to the product will achieve the expected results.

VI.2.Validation shall include dose mapping to establish the distribution of absorbed dose within the irradiation container when packed with product in a defined configuration.

VI.3.The irradiation process specification shall include at least the following:

(a) details of the packaging of the product;

(b) the loading pattern(s) of product within the irradiation container. When a mixture of products is allowed in the irradiation container, particular care shall be taken that there is no underdosing of dense products or shadowing of other products by dense products. Each mixed product arrangement shall be specified and validated;

(c) the loading pattern of irradiation containers around the source (batch mode) or the pathway through the cell (continuous mode);

(d) the maximum and minimum limits of absorbed dose to the product, as well as the associated routine dosimetry;

(e) the maximum and minimum limits of absorbed dose to the irradiation container and the associated routine dosimetry to monitor this absorbed dose;

(f) other process parameters, including dose rate, maximum time of exposure, number of exposures, etc.

When irradiation is outsourced to a third party, items (d) and (e) shall form part of the contract.

VII.   MICROBIOLOGICAL MONITORING

Microbiological monitoring is the responsibility of the manufacturer of the veterinary medicinal product. Environmental monitoring and bioburden monitoring prior to irradiation may be required as specified in the marketing authorisation.

VIII.   SUBCONTRACTING

VIII.1.When treatment by irradiation is subcontracted, the subcontractor shall hold an appropriate manufacturing authorisation.

VIII.2.The manufacturer of the veterinary medicinal product bears the responsibility for the quality of the product, including the attainment of the objective of irradiation. The sub-contractor for the radiation process shall ensure that the dose of radiation required by the manufacturer is delivered to the irradiation container (i.e. the outermost container in which the products are irradiated).

ANNEX VIII

I. Model for confirmation of partial manufacturing

[LETTER HEAD OF MANUFACTURER WHO CARRIED OUT THE MANUFACTURING ACTIVITY]

1.Name of the product and description of the manufacturing stage (e.g. paracetamol tablets, primary packaging into blister packs).

2.Batch number.

3.Name and address of the site carrying out the partial manufacturing.

4.Reference to the written agreement detailing the responsibilities between both parties (in accordance with Article 43).

5.Confirmation statement:

I hereby confirm that the manufacturing stages referred to in the written agreement referred to in Section 4 have been carried out in full compliance with good manufacturing practice requirements applicable in the EU and the terms described in the agreement as provided by [Contract Giver/manufacturer certifying and releasing the batch].

6.Name of the qualified person confirming the partial manufacturing.

7.Signature of qualified person confirming the partial manufacturing.

8.Date of signature.

II.   Model for batch release certificate

[LETTER HEAD OF THE MANUFACTURER CERTIFYING AND RELEASING THE BATCH]

1.Name, strength/potency, dosage form and package size (identical to the text on the finished product package).

2.Batch number of the finished product.

3.Name of the destination country/countries of the batch, at least when within the EU.

4.Certification statement:

I hereby certify that all the manufacturing stages of this batch of finished product have been carried out in full compliance with the good manufacturing practice requirements applicable in the EU and with the requirements of the marketing authorisation [to be added only when batch is exported: of the destination country/countries].

5.Name of the qualified person certifying the batch.

6.Signature of the qualified person certifying the batch.

7.Date of signature.

ANNEX IX

I. REAL TIME RELEASE TESTING

I.1.Under a real time release testing approach, a combination of in-process monitoring and controls may replace end-product testing in the context of the batch release. This approach may only be implemented if it is authorised in the marketing authorisation.

I.2.When designing the real time release testing strategy, the following minimum criteria shall be considered:

— 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 (⁷⁴) and on-line (⁷⁵) 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.