General requirements for quality control
1. A quality control department independent from other departments shall be established and maintained.
2. The quality control department shall be allocated adequate resources, including regarding personnel, premises and equipment, to ensure that quality control can be effectively carried out having regard to the nature and size of the manufacturing operations.
3. The quality control department shall ensure that relevant tests are carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The quality control department is at least responsible for the following:
(a)
establishing, validating and implementing quality control procedures;
(b)
overseeing the control of the reference and retention samples of materials and products, where applicable;
(c)
ensuring the correct labelling of containers of materials and products;
(d)
ensuring the monitoring of the stability of the products;
(e)
participating in the investigation of complaints related to the quality of the product.
All the activities referred to in the first subparagraph, points (a) to (e) shall be carried out in accordance with written procedures and, where necessary, recorded.
4. The head of quality control supervises all quality control procedures. In particular, it shall be responsible for the following tasks:
(a)
approval of specifications, sampling instructions, test methods and other quality control procedures;
(b)
ensuring that required testing is carried out and the associated records evaluated;
(c)
ensuring that the appropriate validations are done;
(d)
approval or rejection of materials used in production, intermediate products, bulk products and finished products;
(e)
ensuring the qualification and maintenance of the premises and equipment used for quality control;
(f)
approval and monitoring of any contract analysts.
5. Personnel involved in quality control shall have access to production areas and to all documents that are needed for the assessment of quality control, including:
(a)
specifications;
(b)
procedures describing sampling and testing;
(c)
testing reports and certificates of analysis;
(d)
procedures for calibration and qualification of instruments and maintenance of equipment and relevant records;
(e)
validation records of test methods, where applicable;
(f)
environmental monitoring data for air, water and other utilities, where required;
(g)
procedures for the investigation of out of specification and out of trend results.
6. Relevant quality control data, such as tests results, yields and environmental data, shall be assessed in a manner permitting trend evaluation. In the case of out of specifications or significant atypical trends, their possible impact on the batches on the market shall be assessed. Where following that assessment it is concluded that the quality of the marketed veterinary medicinal product may be impacted or that shortages of supply can be expected, the competent authorities shall be informed.
7. A quality control check shall be conducted before a finished veterinary medicinal product is released for sale or distribution. That check shall cover all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with the finished product specifications and examination of the final finished pack.
8. Quality control activities can be outsourced provided that the requirements set out in Article 43 are respected. Where tests on materials used in the manufacture of the veterinary medicinal products are outsourced, audits shall be performed by the manufacturer or via a third party to ensure compliance with relevant requirements of good manufacturing practice and the specifications or methods provided.
Sampling
1. A sampling plan shall be established, which shall take into account the risks to the quality of the veterinary medicinal product and address the different materials used in the manufacturing process as well as the various stages of production.
2. Samples shall be representative of the batch of materials or products from which they are taken. The sample taking shall be done in accordance with written procedures that describe at least the following:
(a)
the amount of sample to be taken;
(b)
equipment and containers to be used;
(c)
precautions to be observed to prevent contamination;
(d)
other precautions to be observed, in particular in the case of sterile or noxious materials;
(e)
storage conditions for the samples taken;
(f)
the cleaning instructions for the equipment used.
3. Personnel in charge of taking samples shall receive training on the following:
(a)
techniques and equipment for sampling;
(b)
the risks of cross-contamination;
(c)
precautions to be taken with regard to unstable or sterile substances;
(d)
the need to record any unexpected or unusual circumstance;
(e)
other aspects relevant to the implementation of the sampling procedures.
4. Sample containers shall bear a label indicating the content, batch number, date of sampling and containers from which the samples have been taken. When containers are too small, the use of bar-codes or other means that permit access to that information may be considered.
Sample containers shall be handled and stored in a way that minimises the risk of mix-up or the deterioration of their content. The storage conditions set out in the marketing authorisation shall be applied.
5. Samples shall be kept at the disposal of the competent authorities for the following periods:
(a)
Reference samples and/or retention samples from each batch of finished product shall be retained for at least one year after the expiry date. The reference sample shall be contained in its finished immediate packaging.
However, in the case of large volume presentations, where it is not feasible to retain samples from each batch in its final packaging, the manufacturer shall ensure that sufficient representative samples of each batch are retained and that the container used for storage is composed of the same material as the immediate container in which the product is marketed.
(b)
Reference samples of materials used in the manufacture of veterinary medicinal products, other than solvents, gases or water, shall be kept for at least two years after the release of the product. That period may be shortened if the period of stability of the material, as indicated in the relevant specification, is shorter.
(c)
Samples of packaging materials shall be kept for the duration of the shelf-life of the finished product concerned. For this purpose, retention of printed materials as part of the reference and/or retention samples is also acceptable.
For finished products, reference and retention samples may be regarded as interchangeable.
6. Reference samples shall be of sufficient size to permit the carrying out on at least two occasions of the full analytical controls on the batch in accordance with the marketing authorisation.
7. In cases when the marketing authorisation holder is not the entity responsible for batch release or when several sites are responsible for the manufacture or batch release, the responsibility for the taking and storing of reference and retention samples shall be defined in writing.
8. The ability to do relevant testing throughout the shelf-life of the veterinary medicinal product shall be ensured.
Testing
1. Tests shall be performed to ensure that each batch of the finished product meets the relevant specifications and is in accordance with the terms of the marketing authorisation. Tests shall be performed at appropriate stages of production to control those conditions that are important for the quality of the product. Testing methods shall be validated.
2. The following records shall be kept in connection with the tests performed:
(a)
name of the material or product and, where applicable, dosage form;
(b)
batch number and, where appropriate, the manufacturer or supplier;
(c)
references to the relevant specifications and testing procedures;
(d)
test results, including observations and calculations, and reference to any certificates of analysis;
(e)
dates of testing;
(f)
identification of the persons who performed the testing;
(g)
identification of the persons who verified the testing and the calculations, where appropriate;
(h)
a clear statement of approval or rejection (or other status decision) and the dated signature of the responsible person;
(i)
reference to the equipment used.
3. Reference standards shall be suitable for their intended use. Their qualification or certification status shall be documented. Whenever compendial reference standards from an officially recognised source exist, these shall preferably be used as primary reference standards, unless duly justified. The use of secondary standards shall be documented and their traceability to primary standards shall be demonstrated. Compendial materials shall be used for the purpose described in the appropriate monograph unless otherwise authorised by the relevant competent authority.
4. Materials used for quality control tests, such as reagents, culture media, glassware, and reference standards shall be of appropriate quality and used according to the instructions of the manufacturer unless scientifically justified. The expiry date of reagents and culture media shall be indicated on the label, together with specific storage conditions. Where necessary, identity verification or testing shall be considered upon receipt or before use.
5. Where appropriate, animals used for testing components, materials or products shall be quarantined before use. They shall be maintained and controlled in a manner that assures their suitability for the intended use. In addition, they shall be identified and adequate records kept showing the history of their use.
6. Used microbiological media and strains shall be decontaminated in accordance with a standard procedure and disposed of in a manner to prevent cross-contamination.
On-going stability programme
1. After the marketing authorisation is granted, a programme shall be implemented to verify that, under the relevant storage conditions specified in the marketing authorisation and in the packaging as intended for marketing, the veterinary medicinal product remains within the specifications during the shelf-life (‘on-going stability programme’).
2. The on-going stability programme shall be described in a written protocol which shall detail, among others, the number of batches, the test methods to be used, the acceptance criteria and the testing intervals. The methodology in the on-going stability programme can differ from the approach followed to obtain the stability data submitted in the marketing authorisation application (e.g. different frequency of testing), provided that it is justified.
3. The on-going stability studies shall generally be performed on the finished product as released by the manufacturer, unless a different approach is duly justified. When intermediate products or bulk products are stored for extended periods of time, consideration shall be given to include in the on-going stability programme those batches that have been manufactured from materials stored for longer periods of time. Stability studies on the reconstituted product need not be conducted as part of the on-going stability programme.
4. The number of batches and frequency of testing shall be adequate to allow for trend analysis and shall take into account the risks, such as significant changes in production, significant deviations, reworking or reprocessing operations. At least one batch of the product per strength and packaging type shall be included per year in the on-going stability programme, unless none are produced in a given year or a different frequency is otherwise justified. In particular, where the on-going stability monitoring requires testing using animals and no appropriate alternative techniques are available, the frequency of testing may be adapted. Bracketing and matrixing approaches may be applied if scientifically justified in the protocol.
5. Results of on-going stability studies shall be subject to periodic review and be made available to key personnel and, in particular, to the qualified person. A summary of all the data generated shall be kept.
Technical transfer of testing methods
1. Prior to transferring a test method, the transferring site shall verify that the test method complies with the terms of the marketing authorisation and relevant regulatory requirements.
2. The transfer of testing methods from one laboratory (transferring laboratory) to another laboratory (receiving laboratory) shall be described in a detailed protocol.
3. The protocol shall include, among others, the following elements:
(a)
identification of the testing to be performed and the relevant test method undergoing transfer;
(b)
identification of any specific training requirements;
(c)
identification of standards and samples to be tested;
(d)
identification of any special transport and storage conditions of test items;
(e)
the acceptance criteria.
4. Deviations from the protocol shall be investigated prior to the closure of the technical transfer process. The technical transfer report shall document the comparative outcome of the process and shall identify areas requiring further test method revalidation, if applicable.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
