Commission Implementing Regulation (EU) 2025/2154 of 17 October 2025 laying down good manufacturing practice for active substances used as starting materials in veterinary medicinal products in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council

• CELEX: Implementing Regulation (EU) 2025/2154
• Articles: 78

Article 1 Subject matter and scope

1.   This Regulation lays down the requirements for good manufacturing practice for active substances used as starting materials in veterinary medicinal products (‘active substances’).

2.   This Regulation applies to the manufacture of sterile active substances only up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing shall be performed in accordance with the requirements set out in Annex I to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products.

3.   The manufacture of biological active substances shall comply with the additional requirements set out in Annex II to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products, with the exception of active substances referred to in paragraph 7.

4.   The manufacture of herbal active substances shall be subject to the additional requirements set out in Annex III to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products.

5.   This Regulation, except its Chapter XVII, applies to manufacturers of active substances other than the substances referred to in paragraph 7 of this Article.

6.   Chapter XVII applies to entities involved in the repackaging or relabelling of active substances other than the substances referred to in paragraph 7 of this Article.

7.   This Regulation does not apply to the following active substances:

(a)

active substances to be used in parasiticidal veterinary medicinal products for the target species bees;

(b)

active substances to be used in ectoparasiticidal veterinary medicinal products for external application to animals;

(c)

biological active substances where there is a continuous process from the sourcing or isolation of the active substance from a biological source to the manufacture of the finished product;

(d)

gases where there is a continuous manufacturing and no intermediate storage of gas between the manufacture of the active substance and the manufacture of the veterinary medicinal product is possible.

8.   Chapter VII does not apply to the production of active substance gases performed by air separation.

9.   Articles 48 and 49 do not apply to the production of active substance gases for which the initial stability studies have been replaced by bibliographic data.

10.   Article 50 does not apply to the production of active substance gases, unless otherwise specified.

11.   Whilst meeting the requirements laid down in this Regulation demonstrates compliance with good manufacturing practice, the manufacturer of active substances (the ‘manufacturer’) may implement alternative approaches to the requirements provided for in this Regulation where it is duly justified that the alternative approach is capable of meeting the same objectives and that the quality and purity of the active substance is ensured.

Article 2 Definitions

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

(1)

‘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  ( 4 ) ;

(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 active substance;

(3)

‘intermediate’ means a material produced during steps of the processing of an active substance that undergoes further molecular change or purification before it becomes an active substance;

(4)

‘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;

(5)

‘in-process controls’ means the checks performed during production in order to monitor and, if necessary, adjust the process to ensure that the intermediate or active substance conforms to the required specifications;

(6)

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

(7)

‘batch’ means a defined quantity of materials or product that undergo the same process(es) so that it can be expected to be homogeneous. In the case of continuous manufacturing, a batch corresponds to a defined fraction of the production, characterised by its intended homogeneity;

(8)

‘raw material’ means starting materials, reagents, and solvents intended for use in the production of intermediates or active substances;

(9)

‘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;

(10)

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

(11)

‘quarantine’ means the isolation -physically or by other effective means- of materials, intermediate or active substances whilst awaiting a decision on their release or refusal;

(12)

‘reprocessing’ means introducing an intermediate or active substance, including one that does not conform to standards or specifications, back into the manufacturing process and repeating a crystallisation step or other appropriate chemical or physical manipulation steps that are part of the established manufacturing process; excluding continuation of a process step after an in-process control test has shown that the step is incomplete;

(13)

‘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;

(14)

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

(15)

‘blending’ means the process of combining materials complying with the same specification to produce a homogeneous intermediate or active substance;

(16)

‘primary reference standard’ means a substance that has been shown by an extensive set of analytical tests to be authentic material of high purity and that is obtained from an officially recognised source, or prepared by independent synthesis, or obtained from existing production material of high purity, or prepared by further purification of existing production material;

(17)

‘secondary reference standard’ means a substance of established quality and purity, as shown by comparison to a primary reference standard, used as a reference standard for routine laboratory analysis;

(18)

‘reference sample’ means a sample of a batch of materials used in the manufacture of the active substances used as starting materials in veterinary medicinal products which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned;

(19)

‘reworking’ means subjecting an intermediate or active substance that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or active substance;

(20)

‘mother liquor’ means the residual liquid which remains after the crystallisation or isolation processes;

(21)

‘classical fermentation’ refers to processes that use microorganisms existing in nature or modified by conventional methods such as irradiation or chemical mutagenesis, to produce active substances used as starting materials.

Article 3 Starting point for the manufacture of active substances

1.   The starting point at which the manufacture of an active substance starts shall be determined in accordance with the Annex to this Regulation. The reasons for the implemented approach shall be documented.

2.   From the point determined in accordance with paragraph 1, the requirements set out in this Regulation shall apply.

Article 4 Implementation of a quality management system

1.   Manufacturers shall have in place a comprehensive quality management system designed to ensure the quality of active substances.

2.   Compliance with good manufacturing practice and the terms of the marketing authorisation, when applicable, shall be an essential part of the quality management system.

Article 5 Requirements of the quality management system

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

(a)

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

(b)

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

2.   The manufacturer shall document the quality management system and shall monitor its effectiveness.

3.   The quality management system shall specify:

(a)

the organisational structure of the manufacturer;

(b)

procedures, processes and resources and activities necessary to ensure the quality and purity of the active substance;

(c)

the persons authorised to release active substances and intermediates thereof.

4.   The quality management 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)

there is a quality unit in place, which is independent from production, and that fulfils both quality assurance and quality control responsibilities;

(c)

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

(d)

all quality-related activities are recorded at the time they are performed and that the records identify the person making the entry;

(e)

there is an adequate documentation system that ensures that appropriate specifications are laid down for materials used in the manufacture of the active substance and intermediates thereof, that the production and quality control procedures are clearly defined, and that appropriate records are kept;

(f)

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;

(g)

appropriate controls, including in-process controls and validations are carried out;

(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 active substance are identified, the causes investigated, and appropriate corrective and/or preventive measures are taken;

(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)

no materials are released or used before the satisfactory completion of evaluation by the quality unit unless there are appropriate systems in place to allow for such use;

(l)

procedures are in place for notifying the management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions;

(m)

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

Article 6 Responsibilities of the quality unit

1.   The quality unit shall be responsible for both quality assurance and quality control.

2.   The responsibilities of the quality unit shall include, among others, the following elements:

(a)

release or rejection of active substances and intermediates thereof;

(b)

establishment of a system to release or reject raw materials, intermediates, packaging and labelling materials;

(c)

review of production batch and laboratory control records for critical process parameters before release of the active substance;

(d)

approval of:

(i)

specifications and master production instructions;

(ii)

procedures impacting the quality of active substances or intermediates thereof;

(iii)

intermediate and active substance contract manufacturers;

(iv)

changes potentially impacting the quality of the active substance or intermediates thereof;

(e)

review and approval of all appropriate quality-related documents;

(f)

ensuring that:

(i)

critical deviations are investigated and resolved;

(ii)

self-inspections and/or internal audits are performed;

(iii)

quality-related complaints are investigated and resolved;

(iv)

effective systems are used for maintaining and calibrating critical equipment;

(v)

materials are appropriately tested and the results are reported;

(vi)

stability data to support retest of active substances or intermediates is available, where appropriate;

(g)

performance of product quality reviews referred to in Article 8.

3.   The responsibilities of the quality unit shall be documented in writing and shall not be delegated.

Article 7 Responsibilities of the production unit

The responsibilities for production activities shall be documented in writing, and shall include at least the following elements:

—

preparation, review, approval and distribution of the instructions for the production of active substances or intermediates thereof in accordance with written procedures;

—

production of active substances and, when appropriate, intermediates in accordance with pre-approved instructions;

—

review of all production batch records and ensuring that they are completed and signed;

—

reporting and evaluation of all production deviations, investigation of critical deviations and recording of the conclusions;

—

cleaning and when appropriate disinfection of production premises;

—

performing of the calibrations and keeping the records of those calibrations;

—

maintenance of the premises and equipment and keeping the records of the maintenance activities;

—

review and approval of the validation protocols and reports;

—

evaluation of proposed changes in product, process or equipment;

—

ensuring the qualification of new and modified facilities and equipment.

Article 8 Product quality reviews

1.   Product quality reviews shall be conducted and documented annually for each active substance, taking into account previous reviews and shall include at least a review of the following elements:

(a)

critical in-process controls and critical active substance test results;

(b)

all batches that failed to meet established specifications;

(c)

all critical deviations or non-conformities and the investigation thereof;

(d)

all changes carried out to the manufacturing process or analytical methods;

(e)

the results of the stability monitoring programme;

(f)

all quality-related returns, complaints and recalls;

(g)

adequacy of corrective actions.

2.   The results of the product quality review shall be evaluated and it shall be assessed whether corrective and/or preventive actions are required. Reasons for corrective actions shall be documented and agreed corrective actions shall be completed in a timely and effective manner.

Article 9 Self-inspection

1.   Regular self-inspections shall be conducted to monitor the implementation of the arrangements regarding personnel, premises, equipment, documentation, production, quality control, quality management system, batch release and arrangements to deal with quality-related complaints and recalls.

2.   The self-inspections shall verify the suitability of arrangements referred to in paragraph 1, ensuring that the active substances meet the required quality standards and comply with good manufacturing practice.

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

Article 10 General requirements for personnel

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

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

Article 11 Training

1.   All personnel shall receive initial and continuous training relevant to the tasks assigned. Training on the quality management system and good manufacturing practice shall be provided for personnel whose duties take them into production and storage areas or into control laboratories. Personnel working in areas where contamination is a hazard, such as clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, shall be given specific training. Training shall also include the hygiene programmes referred to in Article 12.

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

Article 12 Hygiene

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

2.   Persons affected by an infectious disease or having open lesions on the exposed surface of the body shall not be involved in activities that could result in compromising the safety or quality of the active substances.

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

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

5.   Eating, drinking, chewing or smoking, or the storage of food, drinks, smoking materials in the production and storage areas shall be prohibited.

Article 13 General requirements for premises

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

2.   The flow of materials and personnel throughout the premises shall be designed to avoid mix-ups or contamination.

3.   Defined areas or control systems shall be in place for the following actions:

(a)

receipt, identification, sampling, and quarantine of incoming materials, pending their release or rejection;

(b)

production operations;

(c)

laboratory operations;

(d)

packaging and labelling operations;

(e)

quarantine before release or rejection of active substances and intermediates thereof;

(f)

sampling of active substances and intermediates thereof;

(g)

storage of released materials;

(h)

holding rejected materials before further disposition (e.g. return, reprocessing or destruction).

4.   Adequate washing and toilet facilities for personnel shall be provided. Washing facilities shall be maintained in clean state and equipped with hot and cold water as appropriate, soap or detergent, and air dryers or single service towels. The washing and toilet facilities shall be separate from manufacturing areas.

5.   Adequate facilities for showering or changing clothes shall be provided, where appropriate.

6.   Laboratory areas and operations shall generally be separated from production areas.

7.   By way of derogation from paragraph 6, laboratory areas, may be located in production areas, provided the following conditions are met:

(a)

operations of the production process do not adversely affect the accuracy of the laboratory measurements;

(b)

the laboratory and its operations do not adversely affect the production process, or the active substances or intermediates thereof.

8.   All utilities affecting product quality shall be qualified and monitored (e.g. steam, gases, compressed air, heating, ventilation and air conditioning). Action shall be taken when limits for those utilities are exceeded. Drawings for those utility systems shall be available.

9.   Adequate ventilation, air filtration and exhaust systems shall be provided, where appropriate. Those systems shall be designed and constructed to minimise risks of contamination and cross-contamination and shall include equipment for control of air pressure, microorganisms, if appropriate, dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention to minimise the risks of contamination and cross-contamination shall be given to areas where active substances are exposed to the environment.

10.   If air is recirculated to production areas, appropriate measures shall be taken to control risks of contamination and cross-contamination.

11.   Fixed pipework shall be appropriately identified by identifying individual lines, documentation, computer control systems, or by alternative means.

12.   Drains shall be of adequate size and shall be provided with an air break or a suitable device to prevent back-flow, where appropriate.

13.   Adequate lighting shall be provided in all areas to facilitate cleaning, maintenance, and proper operations.

14.   Sewage, refuse, and other waste in and from buildings and the immediate surrounding area shall be disposed of in a safe, timely, and sanitary manner. Containers and pipes for waste material shall be clearly labelled.

15.   A site master file shall be prepared for every manufacturing site, which shall provide a high-level description of the premises, of the activities conducted at the manufacturing site and the quality system implemented. The site master file shall follow the template provided for in Annex VI to Implementing Regulation (EU) 2025/2091 on good manufacturing practice for veterinary medicinal products.

Article 14 Water

1.   Water used in the manufacturing process of active substances shall be suitable for its intended use.

2.   Water used in the manufacturing of active substances shall be at least of drinking water quality, unless otherwise justified.

3.   When drinking water quality is insufficient to ensure active substance quality and more stringent water quality specifications are needed, appropriate specifications for physical, chemical, microbiological attributes, objectionable organisms, and endotoxins shall be established.

4.   Where water used in the manufacture of active substances is processed by the manufacturer to achieve a defined quality, the process applied to the water shall be validated and monitored and action limits shall be set to ensure the quality of the water.

5.   Water used in the final isolation and purification steps in the production of a non-sterile active substance intended for the production of a sterile veterinary medicinal product, shall be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

Article 15 Containment

1.   Unless validated inactivation and cleaning procedures are established and maintained, dedicated production areas shall be used when materials of infectious nature or high pharmacological activity or toxicity are involved.

2.   Appropriate measures shall be established and implemented to prevent cross- contamination from among others, personnel or materials moving from one area to another.

3.   Production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials such as biocides and plant protection products shall not take place in premises being used for the production of active substances.

4.   Handling and storage of highly toxic nonpharmaceutical materials shall be separated from active substances.

5.   A comprehensive and effective quality system incorporating adequate quality controls and quality risk management shall be used for determining the necessity for and the extent to which production areas may be used for the production of multiple active substances and to mitigate the risk of contamination.

Article 16 Sanitation and maintenance

1.   Written procedures shall be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and premises.

2.   Written procedures shall be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, cleaning and sanitising agents to prevent the contamination of equipment, raw materials, packaging or labelling materials, active substances or intermediates thereof.

Article 17 Design and construction

1.   Equipment for manufacturing operations of active substances or intermediates thereof shall meet the following conditions:

(a)

be of appropriate design and adequate size, and suitably located and qualified for its intended use;

(b)

be cleaned, sanitised, where appropriate and maintained;

(c)

be constructed so that contact surfaces do not alter the quality of the products beyond the established specifications for the active substance;

(d)

be used within its qualified operating range.

2.   Major equipment and permanently installed processing lines used during the production of active substances or intermediates thereof shall be appropriately identified.

3.   Substances required for the operation of equipment used in manufacturing operations, such as lubricants, heating fluids or coolants, shall not come into contact with the active substances or intermediates thereof. Deviations from this requirement shall be evaluated to check whether there are no detrimental effects to the fitness for purpose of the active substances or intermediates thereof. Wherever possible, food grade lubricants and oils shall be used during the operation of equipment used in manufacturing operations.

4.   Closed or contained equipment shall be used when appropriate. Where open equipment is used, or equipment is opened, appropriate precautions shall be taken to minimise the risk of contamination.

5.   The manufacturer shall ensure that up-to-date drawings are kept for equipment used in manufacturing operations and critical installations such as instrumentation and utility systems.

Article 18 Maintenance and cleaning

1.   Manufacturers shall establish:

(a)

schedules and procedures, including assignment of responsibilities, for the maintenance of equipment used in manufacturing operations;

(b)

written procedures for cleaning of equipment and its subsequent release for use in the manufacture of active substances and intermediates thereof.

2.   The cleaning procedures shall be sufficiently detailed to allow cleaning of each type of equipment in a reproducible and effective manner, and shall include the description of the following:

(a)

assignment of responsibilities for cleaning of equipment;

(b)

cleaning schedules, including, where appropriate, sanitising schedules;

(c)

the methods and materials, including dilution of cleaning agents used to clean equipment;

(d)

instructions for disassembling and reassembling each article of equipment to ensure proper cleaning, where appropriate;

(e)

instructions for the removal or obliteration of previous batch identification;

(f)

instructions for the protection of clean equipment from contamination prior to use;

(g)

inspection of equipment for cleanliness immediately before use, if practical;

(h)

the maximum time that may elapse between the completion of processing and equipment cleaning, where appropriate.

3.   Equipment and utensils shall be cleaned, stored, and, where appropriate, sanitised or sterilised to prevent contamination or carry-over of a material that would alter the quality of the active substances or intermediates thereof beyond the established specifications of the active substances or intermediates thereof.

4.   Where equipment is assigned to continuous production or campaign manufacture of successive batches of the same active substance or intermediate thereof, equipment shall be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants.

5.   Equipment which is not assigned to continuous production or campaign manufacture of successive batches of the same active substance or intermediate thereof shall be cleaned between production of different materials to prevent cross-contamination.

6.   Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents shall be defined and the reasons for choosing them shall be documented.

7.   Equipment shall be identified as to its contents and its cleanliness status.

Article 19 Calibration

1.   Manufacturers shall ensure that the following requirements are met:

(a)

control, weighing, measuring, monitoring and test equipment that is critical for ensuring the quality of the active substances or intermediates thereof is calibrated in accordance with written procedures and an established schedule;

(b)

equipment calibrations are performed using standards which ensure traceability to certified standards, where available;

(c)

records of the calibrations referred to in point (b) are kept;

(d)

the calibration status of equipment that is critical to the quality of the active substances or intermediates thereof is known and verifiable;

(e)

instruments that do not meet calibration criteria are not used.

2.   Deviations from certified standards of calibration on critical equipment shall be investigated to determine the potential impact on the quality of the active substances or intermediates thereof manufactured using the concerned equipment since the last successful calibration.

Article 20 Computerised systems

1.   Computerised systems related to the good manufacturing practices for active substances shall be validated, taking into account the diversity, complexity and criticality of the computerised system.

2.   Appropriate installation qualification and operational qualification shall demonstrate the suitability of computer hardware and software to perform assigned tasks.

3.   Commercially available software that has been qualified shall not require the same level of testing as non-commercially available software. Where an existing computerised system is not validated at the time of installation, a retrospective validation shall be conducted if appropriate documentation is available.

4.   Computerised systems shall have controls preventing unauthorised access, changes to data and omissions in data. All changes in data shall be recorded and reviewed in the audit trail.

5.   Written procedures shall be available for the operation and maintenance of computerised systems.

6.   Where critical data are entered manually, an additional check on the accuracy of the entry shall be performed by a second operator or by the system itself.

7.   Incidents related to computerised systems potentially affecting the quality of the active substances or intermediates thereof, or the reliability of records or test results, shall be recorded and investigated.

8.   Changes to the computerised system shall be made in accordance with a change control procedure and shall be formally approved, documented and tested, where appropriate. Records shall be kept of all changes to the computerised system., including modifications and enhancements made to the hardware, software and any other critical component of the system. Those records shall demonstrate that the computerised system is maintained in a validated state.

9.   A back-up system shall be in place to prevent computerised system breakdowns or failures resulting in the permanent loss of records.

10.   Data protection shall be ensured for all computerised systems.

11.   In addition to the computerised system, data may be recorded by a different means.

Article 21 Documentation system

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

2.   The documentation system shall cover in a comprehensive manner the instructions and specifications related to the manufacture of active substances and intermediates thereof, as well as other documentation relevant to the quality management system and shall ensure that records are made of the activities which may directly or indirectly affect the quality of the active substances or intermediates thereof. The documentation system shall specify the retention period for each of the documents or records.

3.   All production, control, and distribution records of a batch shall be retained for at least 1 year after the expiry date of the batch.

4.   By derogation from paragraph 3, records for active substances with retest dates shall be retained for at least 3 years after the batch is completely distributed.

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

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

7.   Suitable retrieval equipment and a means to produce hard copies shall be readily available in case reduction techniques such as microfilming or electronic records are used to retain specifications, instructions, procedures or records.

8.   During the retention period, the documents and records shall be readily available at the establishment where the activities described in those documents and records occurred.

9.   Electronic signatures on the documents and records shall be authenticated and secure.

Article 22 Specifications

1.   Specifications shall be established and laid down for:

(a)

raw materials;

(b)

intermediates;

(c)

active substances;

(d)

labelling and packaging materials.

2.   Specifications shall be established for any other materials used during the production of active substances and intermediates thereof that could critically impact the quality of active substances and intermediates thereof.

3.   Acceptance criteria shall be established and documented for in-process controls.

Article 23 Equipment cleaning, maintenance and use records

1.   Records of major equipment use, cleaning, sanitisation and sterilisation and maintenance shall be kept. Those records shall include:

(a)

the date and, if appropriate, the time;

(b)

product, and batch number of each batch processed in the equipment;

(c)

the person who performed the cleaning and maintenance.

2.   Individual equipment records are not required for equipment dedicated to manufacture of only one active substance or intermediate thereof, provided that batches follow in traceable sequence.

3.   Records of major equipment use, cleaning, sanitisation or sterilisation, and maintenance may either be part of the batch record or kept separately.

Article 24 Records for raw materials, intermediates, active substance labelling and packaging materials

1.   Adequate records shall be kept to enable the entire history of a batch to be traced.

2.   Receipt and batch processing records shall be kept for each delivery of materials used in the manufacturing, including raw materials, intermediate as well as labelling and packaging materials. Those records shall include:

(a)

the name of the manufacturer of the delivered material;

(b)

identity and quantity of each delivery of each batch of raw materials, intermediates or labelling and packaging materials for active substances;

(c)

the name of the supplier;

(d)

the supplier’s identification number;

(e)

the identification number allocated upon receipt and the date of receipt;

(f)

the results of any test or examination performed and the conclusions thereon;

(g)

records tracing the use of materials;

(h)

documentation of the examination and review of active substance labelling and packaging materials for conformity with established specifications;

(i)

the final decision regarding rejected raw materials, intermediates or active substance labelling and packaging materials.

3.   Master labels shall be maintained for comparison to issued labels.

Article 25 Master production instructions

1.   Master production instructions for each active substance and intermediate thereof shall be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit.

2.   The master production instructions referred to in paragraph (1) shall include:

(a)

the name of the active substance or intermediate thereof being manufactured and an identifying document reference code, if applicable;

(b)

a complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics;

(c)

an accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production shall be included. Variations to the quantities of raw materials or intermediates used shall be included where they are justified;

(d)

the production location and major production equipment to be used;

(e)

detailed production instructions, including:

—

sequences to be followed,

—

ranges of process parameters to be used,

—

sampling instructions and in-process controls with their acceptance criteria, where appropriate,

—

time limits for completion of individual processing steps and the total process, where appropriate,

—

expected yield ranges at appropriate phases of processing or time,

—

where appropriate, special notations and precautions to be followed, or cross references to these,

—

the instructions for storage of the active substance or intermediate thereof to assure its suitability for use, including the labelling and packaging materials and special storage conditions with time limits, where appropriate.

Article 26 Batch production and control records

1.   Batch production records shall be prepared for each active substance and intermediate thereof. Those batch production records shall:

(a)

for each batch include the complete information referred to in paragraph 2;

(b)

be checked before issuance of the record to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction;

(c)

include a reference to the master production instructions being used, in case that batch production record is produced from a separate part of the master production instruction;

(d)

be numbered with a unique batch or identification number and dated and signed when issued. In continuous production, the product code together with the date and time may serve as the unique identifier until the final number is allocated.

2.   Batch production and control records shall include:

(a)

dates and, where appropriate, times of production and control;

(b)

identification of major equipment (e.g. reactors, dryers, mills, etc.) used;

(c)

specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing;

(d)

results recorded for critical process parameters;

(e)

samplings performed;

(f)

signatures of the persons performing and directly supervising or checking each critical step in the operation;

(g)

in-process and laboratory test results;

(h)

yield at appropriate phases or times;

(i)

description of packaging and labelling of the active substance or the intermediate thereof;

(j)

the representative label of active substance or intermediate thereof, if made commercially available;

(k)

any deviation from procedures and instructions or any unusual occurrence which could impact the manufacture or testing of the active substance, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately;

(l)

results of the release testing.

3.   Written procedures shall be established and followed for investigating critical deviations from procedures and instructions or any unusual occurrence which could impact the manufacture or testing of the active substance or the failure of a batch of active substance or intermediate thereof to meet specifications. The investigation shall be extended to other batches that may have been associated with that deviation or failure.

Article 27 Laboratory control records

1.   Laboratory control records shall be prepared for each active substance. Those laboratory control records shall include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays and in particular, the following aspects:

(a)

a description of samples received for testing, including the material name or source, batch number or other distinctive code, date of sampling, and, where appropriate, the quantity and date the sample was received for testing;

(b)

a description of or reference to each test method used;

(c)

a statement of the weight or measure of the sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions;

(d)

a complete record of all raw data generated during each test, in addition to graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested;

(e)

a record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors;

(f)

a statement of the test results and how they compare with established acceptance criteria;

(g)

the signature of the person who performed each test and the dates when the tests were performed;

(h)

the date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

2.   Laboratory control records shall also include complete records on:

(a)

all modifications to an established analytical method;

(b)

periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;

(c)

all stability testing performed on active substances;

(d)

out-of-specification investigations.

Article 28 Batch production and laboratory control records review

1.   Written procedures shall be established and followed for review and approval of batch production records referred to in Article 26 and laboratory control records referred to in Article 27, to ensure compliance of the active substance or intermediate thereof with established specifications before a batch is released.

2.   Production and laboratory control records of non-critical process steps may be reviewed by qualified production personnel or other units following procedures approved by the quality unit.

3.   All deviation, investigation, and out-of-specification reports shall be reviewed, as part of the batch record review, before the batch is released.

4.   The quality unit can delegate the responsibility and authority for release of intermediates to the production unit, except for those intermediates dispatched outside the control of the manufacturer.

Article 29 Handling of materials

1.   Handling of materials including aspects related to the receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection, shall be done in accordance with written procedures or instructions and recorded as appropriate.

2.   Suppliers of materials used in the manufacturing of the active substance shall be approved by the quality unit after verifying the suitability thereof. In case of critical materials, qualification of the suppliers is required. The level of supervision shall be proportionate to the risks posed by the individual materials.

3.   All materials shall be purchased in compliance with the relevant specification.

4.   Where the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer shall be known by the intermediate or active substance manufacturer.

5.   Changes in the source of supply of critical raw materials shall be treated according to Chapter XIII.

Article 30 Receipt and quarantine for incoming materials

1.   Upon receipt, each container or grouping of containers of materials shall be examined visually for correct labelling, including for correlation between the name used by the supplier and the name used by the manufacturer, if these are different.

2.   Damage to containers and any other problem (e.g. evidence of seal tampering or evidence of breaches of package integrity) that may adversely affect the quality of a material shall be investigated.

3.   Incoming materials shall be physically or administratively quarantined immediately after receipt, until their release is authorised by a responsible person, after verification of compliance with the relevant specifications.

4.   Before incoming materials are mixed with existing stocks (e.g. solvents or stocks in silos), they shall be identified as correct, tested, if appropriate, and released. Procedures shall be available to prevent discharging materials erroneously into the existing stock.

5.   Whenever bulk deliveries are made in non-dedicated tankers, the absence of cross-contamination from the tanker shall be assured. Such assurance can be provided by means of one or more of the following elements:

—

a certificate of cleaning,

—

testing for trace impurities,

—

audit of the supplier.

6.   Large storage containers, and their attendant manifolds, filling and discharge lines shall be appropriately identified.

7.   Each container or grouping of containers with incoming materials shall be assigned and identified with a distinctive code, batch, or receipt number. That number shall be used in recording the disposition of each batch.

8.   A system shall be in place to identify the status of each batch during receipt and quarantine.

Article 31 Testing of incoming materials

1.   At least one test shall be performed to verify the identity of each batch of incoming material. A supplier's certificate of analysis may be used in place of performing tests, provided that the manufacturer has a system in place to evaluate suppliers.

2.   Supplier approval shall include an evaluation that provides adequate evidence (e.g. compliance history), that the manufacturer consistently provides material meeting the relevant specifications.

3.   A full analysis shall be conducted on at least three batches of incoming material before reducing in-house testing of that material. That full analysis shall be performed at appropriate intervals and compared with the supplier’s certificates of analysis.

4.   The reliability of certificates of analysis shall be checked at regular intervals.

5.   By way of derogation from paragraph 1, processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the manufacturer’s control do not need to be tested if the supplier’s certificate of analysis is obtained, showing that those materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers shall contribute to establish the identity of those materials. The lack of on-site testing for those materials shall be justified and documented.

Article 32 Sampling of incoming materials

1.   Personnel in charge of taking samples shall receive training on the techniques and equipment for sampling, the risks of cross-contamination, precautions to be taken with regard to unstable or sterile substances, the need to record any unexpected or unusual circumstance as well as other aspects relevant to the implementation of the sampling procedures.

2.   Samples shall be representative of the batch of material from which they are taken. The taking of samples shall be done in accordance with written procedures that describe at least the following:

(a)

the number of containers to be sampled;

(b)

which part of the container to sample;

(c)

the amount of sample to be taken from each container.

3.   The number of containers to sample and the sample size shall be based upon a sampling plan that takes into consideration the following:

(a)

the criticality of the incoming material;

(b)

material variability;

(c)

compliance history of the supplier;

(d)

the amount of sample needed for analysis.

4.   Sampling shall be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

5.   Containers from which samples are collected shall be opened carefully and subsequently reclosed. They shall be marked to indicate that a sample has been taken.

6.   Sample containers shall bear a label indicating the content, batch number, date of sampling and containers from which the samples have been taken.

Article 33 Re-evaluation of materials

All materials shall be re-evaluated as appropriate to determine their suitability for use (e.g. after prolonged storage or exposure to heat or humidity).

Article 34 Production operations

1.   Raw materials for manufacture of active substances or intermediates thereof shall be weighed or measured under appropriate conditions that do not affect their suitability for use.

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

3.   Whenever a material is subdivided for later use in production operations, the container receiving the material shall be suitable and shall be identified so that the following information is available:

(a)

material name or item code;

(b)

receiving or control number;

(c)

weight or measure of material in the new container;

(d)

re-evaluation or retest date if appropriate.

4.   Critical activities, including the critical weighing, measuring, or subdividing operations shall be verified or subjected to an equivalent control. Prior to use, the manufacturer shall ensure that its production personnel verifies that the materials are those specified in the batch record for the intended active substance or intermediate thereof.

5.   Actual yields shall be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges shall be established based on previous laboratory, pilot scale or manufacturing data. Deviations in yield associated with critical process steps shall be investigated to determine their impact or potential impact on the resulting quality of the affected batches.

6.   Any deviation in yield shall be documented and explained. Any critical deviation shall be investigated.

7.   The processing status of major units of equipment shall be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

8.   Materials to be reprocessed or reworked shall be appropriately controlled to prevent unauthorised use.

Article 35 Time limits

Whenever time limits are specified in the master production instructions, those time limits shall be met to ensure the quality of active substances and intermediates thereof. Time limit deviations shall be documented and evaluated.

Article 36 In-process controls and in-process sampling

1.   Written procedures shall be established to monitor the progress and control the performance of processing steps that cause variability in the quality of active substances and intermediates thereof. In-process controls and their acceptance criteria shall be defined based on the information gained during the development stage or historical data.

2.   The acceptance criteria and the type and extent of testing may depend on:

(a)

the nature of the intermediate or active substance being manufactured;

(b)

the reaction or process step being conducted;

(c)

the degree to which the process introduces variability in the quality of the active substance or the intermediate thereof.

3.   Less stringent in-process controls may be appropriate in early processing steps, whereas more stringent controls may be appropriate for later processing steps (e.g. isolation and purification steps).

4.   Critical in-process controls and critical process monitoring, including the control points and methods, shall be stated in writing and approved by the quality unit.

5.   In-process controls may be performed by qualified personnel of the production department. The process may be adjusted without prior quality unit approval in case those adjustments are made within established limits approved by the quality unit. All tests and results shall be fully documented as part of the batch record.

6.   Written procedures shall describe the sampling methods for in-process materials, intermediates and active substances. These procedures shall be designed to prevent contamination of the sampled material and of other intermediates or active substances. Procedures shall be established to ensure the integrity of samples after collection.

7.   Out-of-specification investigations shall be performed.

8.   By way of derogation from paragraph 7, out-of-specification investigations are not required for in-process tests that are performed for the purpose of monitoring or adjusting the process.

Article 37 Blending batches of intermediates or active substances

1.   Out-of-specification batches shall not be blended with other batches for the purpose of meeting specifications.

2.   Each batch incorporated into the blend shall:

(a)

have been manufactured using an established process; and

(b)

have been individually tested and found to meet appropriate specifications prior to blending.

3.   Acceptable blending operations include:

(a)

blending of small batches to increase batch size;

(b)

blending of tailings (e.g. relatively small quantities of isolated material) from batches of the same intermediate or active substance to form a single batch.

4.   Blending processes shall be adequately controlled and documented and the blended batch shall be tested for conformity to established specifications, where appropriate.

5.   The batch record of the blending process shall allow traceability back to the individual batches that compose the blend.

6.   Where physical attributes of the active substance are critical (e.g. active substances intended for use in solid oral dosage forms or suspensions), blending operations shall be validated to show homogeneity of the combined batch. Validation shall include testing of critical attributes (e.g. particle size distribution, bulk density, and tap density) that may be affected by the blending process.

7.   Where the blending may adversely affect stability, stability testing of the final blended batches shall be performed.

8.   The expiry or retest date of the blended batch shall be based on the manufacturing date of the oldest tailings or batch in the blend.

Article 38 Contamination control

1.   Carryover of residual materials into successive batches shall not result in the carryover of degradants or microbial contamination that may adversely alter the established active substance’s impurity profile.

2.   Production operations shall be conducted in a manner that prevents contamination of active substances or intermediates thereof by other materials.

3.   Precautions to avoid contamination shall be taken for the handling of active substances after purification.

Article 39 General requirements concerning packaging and labelling

1.   Written procedures shall be put in place to describe the receipt, identification, quarantine, sampling, examination or testing, release, and handling of packaging and labelling materials.

2.   Packaging and labelling materials shall conform to established specifications. Packaging and labelling materials that do not comply with the specifications shall be rejected to avoid their use in operations for which they are unsuitable.

Article 40 Containers

1.   Containers shall provide adequate protection against deterioration or contamination of the active substances or intermediates thereof that may occur during transportation and storage.

2.   Containers shall be clean and, where indicated by the nature of the active substances or intermediates thereof, sanitised to ensure that they are suitable for their intended use. Those containers shall not be reactive, additive, or absorptive so as to alter the quality of the active substances or intermediates thereof beyond the specified limits.

3.   Whenever containers are re-used, they shall be cleaned in accordance with documented procedures and all previous labels shall be removed or defaced.

Article 41 Label issuance and control

1.   Access to the areas where labels are stored shall be limited to authorised personnel.

2.   Procedures shall be used to reconcile the quantities of labels issued, used and returned, and to identify discrepancies between the number of containers labelled and the number of labels issued. Such discrepancies shall be investigated, and the investigation shall be approved by the quality unit.

3.   All excess labels bearing batch numbers or other batch-related printing shall be destroyed. Returned labels shall be maintained and stored in a manner that provides proper identification and prevents mix-ups of labels.

4.   Obsolete and outdated labels shall be destroyed, and such disposal be recorded.

5.   Printing devices used to print labels for packaging operations shall be controlled to ensure that all imprinting conforms to the print specified in the batch production record.

6.   Printed labels issued for a batch shall be carefully examined for proper identity and conformity with specifications in the master production record. The results of this examination shall be documented.

7.   A printed label as used for the batch concerned shall be included in the batch production record.

Article 42 Packaging and labelling operations

1.   Documented procedures shall be put in place to ensure that correct packaging materials and labels are used.

2.   Appropriate measures shall be implemented to avoid mix ups of packaging materials or labels. There shall be physical or spatial separation from operations involving other intermediates or active substances.

3.   Labels used on containers of intermediates or active substances shall indicate the name or identifying code, the batch number of the product, and storage conditions, when that information is critical to assure the quality of the active substance or intermediates thereof.

4.   Whenever the intermediate or the active substance is intended to be transferred outside the control of the manufacturer, the label shall also include the name and address of the manufacturer, quantity of contents, special transport conditions and any special legal requirements. For intermediates or active substances with an expiry date, the expiry date shall be indicated on the label and on the certificate of analysis. For intermediates or active substances with a retest date, the retest date shall be indicated on the label and on the certificate of analysis.

5.   Packaging and labelling premises shall be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This inspection shall be documented in the batch production records, the facility log, or other documentation system.

6.   Packaged and labelled intermediates or active substances shall be examined to ensure that containers and packages in the batch have the correct label. That examination shall be part of the packaging operation. Results of those examinations shall be recorded in the batch production or control records.

7.   Intermediate or active substance containers that are transported outside of the manufacturer's control shall be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.

Article 43 Storage conditions and warehousing procedures

1.   All materials used for the manufacturing of active substances shall be stored and handled under appropriate conditions (e.g. controlled temperature and humidity, where necessary) to ensure their quality and prevent degradation, contamination, and cross-contamination.

2.   Whenever storage conditions are critical for the maintenance of material characteristics, records of those conditions shall be maintained.

3.   Materials stored in fiber drums, bags or boxes shall be stored off the floor and, where appropriate, suitably spaced to permit cleaning and inspection.

4.   Materials shall be stored for a period of time that has no adverse effect on their quality. Materials shall be controlled so that the oldest stock is used first.

5.   Certain materials in suitable containers may be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

6.   Rejected materials shall be identified and controlled under a quarantine system designed to prevent their unauthorised use in manufacturing.

7.   Separated areas shall be provided for the storage of quarantined, rejected, returned, or recalled materials.

Article 44 Distribution procedures

1.   Active substances and intermediates thereof shall only be released for distribution to third parties after they have been released by the quality unit.

2.   Active substances and intermediates thereof can be transferred under quarantine to another unit under the manufacturer’s control when authorised by the quality unit and if appropriate controls and documentation are in place.

3.   Active substances and intermediates thereof shall be transported in a manner that does not adversely affect their quality.

4.   Special transport or storage conditions for an active substance or intermediate shall be stated on the label.

5.   In case of outsourced activities as referred to in Chapter XVI, the manufacturer (‘contract giver’) shall ensure that adequate information is transmitted to the contractor (‘contract acceptor’) for the performance of the outsourced activities and that the contract acceptor follows the appropriate transport and storage conditions.

6.   A system shall be in place by which the distribution of each batch of intermediate or active substance can be traceable to permit its recall.

Article 45 General controls

1.   All specifications, sampling plans and test procedures shall be scientifically justified and appropriate to ensure that raw materials, intermediates, active substances and labels and packaging materials conform to established standards of quality and purity.

2.   Specifications and test procedures shall be in compliance with the terms of the marketing authorisation. There can be specifications in addition to those in the terms of the marketing authorisation.

3.   Specifications, sampling plans and test procedures, including changes to them, shall be drafted by the appropriate organisational unit and reviewed and approved by the quality unit.

4.   Appropriate specifications shall be established for active substances in accordance with accepted standards and consistent with the manufacturing process.

5.   The specifications for the active substance shall include a control of the impurities (e.g. organic impurities, inorganic impurities and residual solvents). If the active substance has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms shall be established and met. If the active substance has a specification for endotoxins, appropriate action limits shall be established and met.

6.   Laboratory controls shall be monitored and documented at the time of performance.

7.   Procedures shall be established for the investigation and documentation of out-of-specification results. Those procedures shall require analysis of the data, assessment of the criticality of the out-of-specification result, allocation of the tasks for corrective actions and conclusions. Any re-sampling or retesting after out-of-specification results shall be performed according to a documented procedure.

8.   Procedures shall be established for the preparation of reagents and standard solutions and the labelling thereof. Expiry dates shall be applied as appropriate for analytical reagents or standard solutions.

9.   Primary reference standards shall be suitable for their intended use. The source of each primary reference standard shall be documented. Records shall be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations.

10.   Primary reference standards obtained from an officially recognised source may be used without testing if stored under conditions consistent with the supplier’s recommendations.

11.   Where a primary reference standard is not available from an officially recognised source, an “in-house primary reference standard” shall be established. Appropriate testing shall be performed to establish fully the identity and purity of the in-house primary reference standard. Appropriate documentation of that testing shall be maintained.

12.   Secondary reference standards shall be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard shall be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard shall be periodically requalified in accordance with a written protocol.

Article 46 Testing

1.   Appropriate laboratory tests to determine conformity to specifications shall be conducted for each batch of active substance and intermediates thereof.

2.   An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process shall be established for each active substance. The impurity profile shall include:

(a)

the identity of the impurity or some qualitative analytical designation (e.g. retention time);

(b)

the range of each identified impurity;

(c)

a classification of each identified impurity (e.g. inorganic, organic, solvent).

3.   By way of derogation from paragraph 2, impurity profiles are not necessary for active substances from herbal or animal tissue origin.

4.   The impurity profile shall be compared at appropriate intervals against the impurity profile in the terms of the marketing authorisation or compared against historical data in order to detect changes to the active substance resulting from modifications in raw materials, equipment operating parameters, or the production process.

5.   Appropriate microbiological tests shall be conducted on each batch of intermediate and active substance where microbial quality is specified.

Article 47 Certificates of analysis

1.   Upon request, certificates of analysis shall be issued for each batch of intermediate or active substance.

2.   The certificate of analysis shall contain at least:

(a)

the name of the intermediate or active substance including, where appropriate, its grade;

(b)

the batch number;

(c)

the date of release;

(d)

the expiry date for intermediates or active substances with an expiry date;

(e)

the retest date for intermediates or active substances with a retest date;

(f)

each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained, if appropriate.

3.   Certificates shall be dated and signed by authorised personnel of the quality unit and shall include the name, address and telephone number of the original manufacturer.

4.   Where the analysis has been carried out by entities involved in repackaging or reprocessing, the certificate of analysis shall include the name, address and telephone number of the entity involved in repackaging or reprocessing and a reference to the name of the original manufacturer.

5.   Whenever new certificates are issued by or on behalf of entities involved in repackaging or reprocessing, those certificates shall include the name, address and telephone number of the laboratory that performed the analysis. They shall also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which shall be attached.

Article 48 On-going stability monitoring programme

1.   Manufacturers shall put in place a documented, on-going stability programme to monitor the stability data of active substances. The results shall be used to confirm appropriate storage conditions and retest or expiry dates.

2.   The test procedures used in stability studies shall be appropriate for the active substance and validated.

3.   Stability samples shall be stored in containers that simulate the market container.

4.   The first three production scale batches shall be placed on the on-going stability programme to confirm the retest or expiry date.

5.   By way of derogation from paragraph 4, where data from previous studies show that the active substance is expected to remain stable for at least two years, fewer than three batches may be used.

6.   After the first three production scale batches being placed on the on-going stability programme, at least one batch per year of the active substance manufactured shall be included into the on-going stability programme, unless none are produced in a given year or a different frequency is otherwise justified.

7.   In case of active substances with short shelf life, stability testing shall be done more frequently. When data exist confirming that the stability of the active substance is not compromised, elimination of specific test intervals may be considered.

8.   Where appropriate, the stability testing of active substances shall be performed in accordance with the conditions set out in the Guideline on stability: stability testing of new veterinary drug substances and medicinal products  ( 5 ) .

Article 49 Expiry and retest dating

1.   Where an intermediate is intended to be transferred outside the control of the manufacturer and an expiry or retest date is assigned, supporting stability information shall be available (e.g. published data, test results).

2.   The expiry or retest date of an active substance shall be based on an evaluation of data derived from stability studies.

3.   Preliminary active substance expiry or retest dates may be based on pilot scale batches where the following conditions are fulfilled:

(a)

the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a production scale;

(b)

the quality of the active substance represents the material to be made on a production scale.

Article 50 Retention of samples

1.   Reference samples shall be kept for the purpose of potential future evaluation of the quality of batches of active substance and not for future stability testing purposes.

2.   Reference samples of each active substance batch shall be retained for one year after the expiry date of the batch, or for three years after distribution of the batch, whichever is the longest.

3.   For active substances with retest dates, reference samples shall be retained for three years after the batch is completely distributed by the manufacturer.

4.   Reference samples shall be stored in the same packaging system in which the active substance is stored or in one that is equivalent to or more protective than the marketed packaging system.

5.   Sufficient quantities shall be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.