Commission Directive 2009/9/ECShow full title

C. PRODUCTION AND CONTROL OF STARTING MATERIALS

For the purposes of this paragraph “starting materials” means all components used in the production of the immunological veterinary medicinal product. Culture media consisting of several components used for production of the active substance shall be regarded as one starting material. Nevertheless, the qualitative and quantitative composition of the any culture media shall be presented in so far as the authorities consider that this information is relevant to the quality of the finished product and any risks that might be posed. If materials of animal origin are used for preparation of these culture media, the animal species and the tissue used have to be included.

The dossier shall include the specifications, information on the tests to be conducted for the quality control of all batches of starting materials and results for a batch for all components used and shall be submitted in accordance with the following provisions.

1. Starting materials listed in pharmacopoeias

The monographs of the European Pharmacopoeia shall be applicable to all starting materials appearing in it.

In respect of other substances, each Member State may require observance of its own national pharmacopoeia with regard to products manufactured in its territory.

Constituents fulfilling the requirements of the European Pharmacopoeia or the pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with Article 12(3)(i). In this case the description of the analytical methods may be replaced by a detailed reference to the pharmacopoeia in question.

Colouring matter shall, in all cases, satisfy the requirements of Directive 78/25/EEC.

The routine tests carried out on each batch of starting materials must be as stated in the application for marketing authorisation. If tests other than those mentioned in the pharmacopoeia are used, proof must be supplied that the starting materials meet the quality requirements of that pharmacopoeia.

In cases where a specification or other provisions contained in a monograph of the European Pharmacopoeia or in the pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the applicant for marketing authorisation. The alleged insufficiency shall be reported to the authorities responsible for the pharmacopoeia in question.

In cases where a starting material is described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted; in such cases, the applicant shall submit a copy of the monograph accompanied where necessary by the validation of the test procedures contained in the monograph and by a translation where appropriate.

When starting materials of animal origin are used, they shall comply with the relevant monographs including general monographs and general chapters of the European Pharmacopoeia. The tests and controls conducted shall be appropriate to the starting material.

The applicant shall supply documentation to demonstrate that the starting materials and the manufacturing of the veterinary medical product is in comply with the requirements of the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, as well as with the requirements of the corresponding monograph of the European Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant monograph of the European Pharmacopoeia, may be used to demonstrate compliance.

2. Starting materials not listed in a pharmacopoeia

2.1. Starting materials of biological origin

The description shall be given in the form of a monograph.

Whenever possible, vaccine production shall be based on a seed lot system and on established cell seeds. For the production of immunological veterinary medicinal products consisting of serums, the origin, general health and immunological status of the producing animals shall be indicated and defined pools of source materials shall be used.

The origin, including geographical region, and history of starting materials shall be described and documented. For genetically engineered starting materials this information shall include details such as the description of the starting cells or strains, the construction of the expression vector (name, origin, function of the replicon, promoter enhancer and other regulator elements), control of the sequence of DNA or RNA effectively inserted, oligonucleotidic sequences of plasmid vector in cells, plasmid used for cotransfection, added or deleted genes, biological properties of the final construct and the genes expressed, copy number and genetic stability.

Seed materials, including cell seeds and raw serum for anti-serum production shall be tested for identity and extraneous agents.

Information shall be provided on all substances of biological origin used at any stage in the manufacturing procedure. The information shall include:

• details of the source of the materials,

• details of any processing, purification and inactivation applied, with data on the validation of these process and controls during production,

• details of any tests for contamination carried out on each batch of the substance.

If the presence of extraneous agents is detected or suspected, the corresponding material shall be discarded or used in very exceptional circumstances only when further processing of the product ensures their elimination and/or inactivation; elimination and/or inactivation of such extraneous agents shall be demonstrated.

When cell seeds are used, the cell characteristics shall be shown to have remained unchanged up to the highest passage level used for the production.

For live attenuated vaccines, proof of the stability of the attenuation characteristics of the seed has to be given.

Documentation shall be supplied to demonstrate that the seed materials, cell seeds, batches of serum and other material originating from animal species relevant for the transmission of TSE comply with the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products, as well as with the corresponding monograph of the European Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant monograph of the European Pharmacopoeia, can be used to demonstrate compliance.

When required, samples of the biological starting material or reagents used in the testing procedures shall be provided to enable the competent authority to arrange for check tests to be carried out.

2.2. Starting materials of non-biological origin

The description shall be given in the form of a monograph under the following headings:

• the name of the starting material meeting the requirements of point 2 of Section A shall be supplemented by any trade or scientific synonyms,

• the description of the starting material, set down in a form similar to that used in a descriptive item in the European Pharmacopoeia,

• the function of the starting material,

• methods of identification,

• any special precautions which may be necessary during storage of the starting material and, if necessary, its storage life shall be given.