General requirements for production
1. Manufacturing operations (including packaging operations) and controls shall follow clearly defined procedures designed to ensure the quality of the product and compliance with the requirements set in the relevant manufacturing authorisation and marketing authorisation.
2. Manufacturing steps that may have an impact on the quality or reproducibility of the production, including significant changes thereto, shall be validated. Periodic re-validation shall be required to ensure that such manufacturing processes remain capable of achieving the intended results. Process validation shall comply with the requirements laid down in Annex V.
3. Manufacturing processes shall be duly documented and reviewed regularly, and they shall be improved as appropriate. The effects of changes to the manufacturing process on the quality of the finished product and in relation to the need to ensure consistent production shall be considered prior to the implementation of any changes. No change from the specifications and processes described in the dossier supporting the marketing authorisation shall be implemented before the relevant approval is obtained from the competent authorities, with the exception of variations not requiring assessment in accordance with Article 61 of Regulation (EU) 2019/6.
4. Adequate and sufficient resources shall be made available for the in-process controls.
5. Any deviation from instructions or procedures shall be avoided as far as possible. If a deviation occurs, it shall be approved in writing by a responsible person after having assessed the impact thereof on quality, safety and efficacy with the involvement of the qualified person as appropriate. Deviations shall be investigated to identify the root cause and to implement corrective and preventive measures as appropriate.
6. The manufacturer shall report to the marketing authorisation holder any constraints in manufacturing operations that may result in an abnormal restriction in the supply of the veterinary medicinal product.
Handling of materials and products
1. Handling of materials and products, including aspects related to the receipt, quarantine, sampling, storage, labelling and packaging, shall be done in accordance with written procedures or instructions and recorded as appropriate.
2. All incoming materials shall be checked to ensure that the consignment corresponds to the order.
3. Containers shall be cleaned where necessary. Damage to containers and any other problem (e.g. evidence of seal tampering or evidence of breaches of package integrity) that may adversely affect the quality of the material shall be investigated, recorded and reported to the department responsible for quality control.
4. Transport conditions for bulk products, intermediate products and samples shall be verified to ensure compliance with any specified conditions.
5. Incoming materials shall be physically or administratively quarantined immediately after receipt, until their release is authorised by a responsible person, after verification of compliance with the relevant specifications. If one material delivery is made up of different batches, each batch shall be considered separately for the purposes of sampling, testing and release.
6. All materials shall be stored under appropriate conditions to ensure the quality and in an orderly fashion to permit batch segregation (physical or electronic) and stock rotation.
7. Containers shall be labelled appropriately, including:
(a)
the designated name of the product and internal code reference, where applicable;
(b)
the batch number given at receipt;
(c)
where appropriate, the status of the content (e.g. in quarantine, on test, released, rejected);
(d)
where appropriate, an expiry date beyond which retesting is necessary.
Where fully computerised storage systems are used, all the information referred to in points (a) to (d) does not need to appear in a legible form on the label.
8. At all times during the manufacturing process, all materials, bulk containers, major items of equipment and, where appropriate, rooms used shall be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable), and batch number. Where applicable, this indication shall also mention the stage of production.
9. Special precautions shall be taken when handling dry materials or products to prevent the generation and dissemination of dust, particularly for highly active or sensitising materials.
Qualification of suppliers and compliance with specifications
1. Suppliers of materials used in the manufacture of the veterinary medicinal product shall be approved after verifying the suitability thereof. In the case of critical materials, the qualification of the suppliers shall be required. The level of supervision of the suppliers shall be proportionate to the risks to the quality of the product posed by the individual materials.
2. The quality requirements (specifications) for the materials used in the manufacture of veterinary medicinal products shall be agreed with the supplier and documented.
3. Compliance with the requirements set out in the marketing authorisation shall be verified by means of appropriate testing. The level of supervision and further testing required shall be proportionate to the risks. The testing strategy shall be justified and, as a minimum, an identity check of each batch shall be performed by means of tests performed on samples taken from all the containers. Sampling a proportion of the containers shall only be acceptable when validated procedures based on quality risk management principles are in place to ensure the correct labelling of containers, and potential risks to the quality are addressed, for example through the qualification of the supplier.
At appropriate intervals, having regard to the risks, a full analysis of the active substances and other critical materials shall be performed and the results shall be compared with the manufacturer or supplier’s certificate of analysis in order to check the reliability of the latter. The testing may be outsourced. If that testing identifies any discrepancy, an investigation shall be performed and appropriate measures taken. The acceptance of certificates of analysis from the material manufacturer or supplier shall be discontinued until those measures are implemented.
4. Sufficient experience with the relevant supplier or manufacturer of active substances, including assessment of batches previously received and the history of compliance, shall be required before reducing the in-house testing. Any significant change in the manufacturing or testing processes of the active substances shall also be considered as a relevant factor.
5. Audits at the sites of manufacturers and distributors of active substances shall be conducted at appropriate intervals following a risk-based approach to confirm that they comply with good manufacturing practice and good distribution practice and with the specifications provided. Specific consideration shall be given to potential cross-contamination from other materials on site. Deficiencies shall be clearly identified and corrective and preventive actions shall be implemented as appropriate.
Prevention of cross-contamination
1. The production of non-medicinal products shall generally be avoided in areas and with equipment destined for the production of veterinary medicinal products, unless measures to prevent cross-contamination are applied in an effective manner. In particular, the production or storage of chemical substances used in biocides and plant protection products shall be avoided in areas used for the manufacture or storage of veterinary medicinal products, except where the same substance and its grade is also used for manufacture of veterinary medicinal products.
2. Where veterinary medicinal products are produced in an area shared with non-medicinal products, good manufacturing practice for medicinal products shall be implemented in the area.
3. Operations on different products shall not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.
4. Before any manufacturing operation starts, steps shall be taken to ensure that the work area and the equipment are clean and free from any materials, products, product residues or documents not required for the current operation. Mix-ups of materials shall be prevented.
5. At every stage of production, products and materials shall be protected from microbial and other contamination. The risk of cross-contamination shall be assessed having regard to the characteristics of the product and the manufacturing process. The risk of accidental cross-contamination resulting from the uncontrolled release of dust, gases, vapours, aerosols, genetic material or organisms from active substances or other materials used in the production, from residues on equipment and from operators’ clothing shall be assessed.
6. Measures to prevent cross-contamination identified on the basis of quality risk management principles shall be put in place. Measures that may be considered to prevent cross-contamination include:
(a)
the dedication of a whole manufacturing site or a self-contained production area on a campaign basis (separation in time) followed by a cleaning process of validated effectiveness;
(b)
the use of segregated areas;
(c)
the use of closed systems for processing and for material or product transfer;
(d)
the use of airlocks and pressure cascade to confine potential airborne contaminants within a specified area;
(e)
the use of physical barrier systems, including isolators, as containment measures;
(f)
the dedication of specific equipment or certain parts thereof (e.g. filters) to a given type of product with a specific risk profile;
(g)
the utilisation of single use disposable technologies;
(h)
the implementation of validated cleaning or decontamination procedures adapted to the specific characteristics of the product and of the manufacturing process. The cleaning or decontamination procedures that are necessary, including the frequency thereof, shall be determined on the basis of a risk-assessment;
(i)
other suitable organisational measures, such as keeping specific protective clothing inside areas where products at high-risk of contamination are processed, implementing adequate measures for the handling of waste, contaminated rinsing water and soiled gowning, or imposing restrictions on the movement of personnel.
7. The control strategy shall address all the potential risks, including measures at the level of the premises, equipment and personnel, controls on materials used in the manufacture, implementation of effective sterilisation and sanitisations procedures, and adequate monitoring systems. The totality of the measures applied shall ensure the absence of contamination of the products manufactured within the manufacturing site. Sole reliance shall not be placed on any terminal process or finished product test.
8. The effectiveness of the measures implemented shall be reviewed periodically according to set procedures. This assessment shall lead to the implementation of corrective and preventive actions where necessary.
Packaging operations
1. The name and batch number of the product being handled shall be displayed at each packaging station or line.
2. Containers for filling shall be clean before being filled. Filling and sealing shall be followed as quickly as possible by labelling. If it is not possible, appropriate procedures shall be applied to avoid mix-ups or mislabelling.
3. The correct performance of printing operations (for example code numbers, expiry dates) shall be checked and recorded. Printed and embossed information on packaging materials shall be clear and resistant to fade or erasure.
4. Checks shall be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.
5. Appropriate measures shall be implemented to avoid mix ups, such as storing and transporting cut labels and other loose printed materials in separate closed containers. Special care shall be taken when using cut-labels and when over-printing is carried out off-line. To avoid mix-ups, roll-feed labels are generally preferable to cut-labels.
6. The following controls shall be performed on the product during packaging operations:
(a)
general appearance of the packages;
(b)
whether the packages are complete;
(c)
whether the correct products and packaging materials are used;
(d)
whether any over-printing is correct;
(e)
correct functioning of line monitors.
Samples taken away from the packaging line shall not be returned.
7. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and packaging materials and the number of units produced shall be investigated and resolved before the release of the product.
8. Outdated or obsolete immediate packaging material or printed packaging material shall be destroyed and such disposal recorded. A documented procedure shall be followed if un-coded printed materials are returned to stock.
Rejected, recovered and returned materials
1. Rejected materials shall be clearly marked as such and stored separately in restricted areas. They shall either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken, it shall be approved and recorded by authorised personnel.
2. The reprocessing of rejected materials can only be accepted exceptionally and provided that the quality of the final product is not affected and that the specifications set out in the marketing authorisation are met. The recovery of materials conforming to the required specifications from a distinct batch is only possible after an evaluation of the risks, including any possible effect on the shelf-life. Records shall be kept.
3. The need for additional testing of any finished product which has been reprocessed, or into which a reprocessed material has been incorporated, shall be evaluated by the quality control department.
4. Returned products, which have left the control of the manufacturer, shall be destroyed, unless their quality is confirmed by the quality control department. The nature of the product, its condition and history, any special storage conditions, and the time elapsed since it was issued shall be taken into account in that assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for re-issue or re-use. Any action taken shall be recorded.
Use of ionising radiation
The use of ionising radiation in the manufacture of veterinary medicinal products shall comply with the additional requirements set out in Annex VII.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
