Documentation system
1. A documentation system that is adequate to achieve the objectives of the pharmaceutical quality system shall be established and maintained.
2. The documentation system shall cover in a comprehensive matter the instructions and specifications as well as other documentation relevant to the pharmaceutical quality system and shall ensure that records of the activities which may, directly or indirectly, affect the quality of the veterinary medicinal products are kept.
3. The content of documents shall be unambiguous and be kept up to date.
4. Documentation may be kept in a variety of forms and the requirements set out in this Chapter are applicable irrespective of the 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.
Specifications and instructions
1. Specifications and instructions shall be laid down in an orderly fashion and shall be clearly drafted.
2. The specifications for the materials used in the production of veterinary medicinal products and for the finished product, as well as the manufacturing instructions shall be adequate to ensure compliance with the terms of the marketing authorisation and the required level of quality. In particular, the following shall be duly documented:
(a)
specifications for active substances and other substances used in the manufacture of the veterinary medicinal product and for immediate packaging materials, including the following:
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a description of the active substances or other substances used, including any relevant information required to avoid risk of error (e.g. use of internal codes), and identification of the approved supplier(s). Where relevant, reference to a pharmacopeial monograph shall be provided;
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the quality and quantitative requirements as well as acceptance criteria, as appropriate;
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instructions for sampling and testing, as appropriate;
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storage conditions and, where applicable, any special handling precautions;
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the maximum period of storage;
(b)
specifications for intermediate products and bulk products, including release criteria and the maximum period of storage, shall be set out for critical stages and when those products are purchased or dispatched;
(c)
specifications for finished products, in particular:
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the name or identification of the product and, where applicable, the reference code;
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a description of the pharmaceutical form and packaging;
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instructions for sampling and testing;
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the qualitative and quantitative requirements with acceptance limits;
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storage conditions and, where applicable, any special handling precautions;
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the shelf-life;
(d)
manufacturing instructions (including a description of the principal equipment to be used) and in-process controls, including the following:
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the name of the product, with a product reference code relating to its specification;
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a description of the pharmaceutical form, strength of the product and batch size;
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a list of all materials to be used and the relevant amounts of each;
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an indication of the expected final yield with the acceptable limits and, where applicable, of relevant intermediate yields;
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an indication of the location where the relevant step should take place and the principal equipment to be used;
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an indication of or reference to the methods to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising);
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detailed stepwise instructions to be followed (e.g. verification that equipment and workstation is clear of previous products, checks on materials, pre-treatments, sequence for adding materials, critical process parameters such as time, temperature, etc.);
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instructions for any in-process controls, together with their limits;
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where necessary, the requirements for bulk storage of the products, including the container, labelling and, where applicable, special storage conditions;
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any special precautions to be observed;
(e)
packaging instructions for each veterinary medicinal product and pack size, including:
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the name of the product as well as the batch number of the bulk product and finished product;
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a description of its pharmaceutical form, and strength where applicable;
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the pack size expressed in terms of the number, weight or volume of the product in the final container;
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a complete list of all the packaging materials required, including quantities, sizes and types, with the code or reference number relating to the specification of each packaging material;
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relevant instructions with an indication of the equipment to be used, and relevant precautions, including the need for a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;
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details of in-process controls with instructions for sampling and acceptance limits.
3. Documents containing specifications and instructions, including any changes thereto, shall be approved, signed and dated by authorised persons and the date of entry into operation shall be defined. Steps shall be taken to ensure that only the current version of a document is used.
Records
1. Adequate records shall be kept to enable the entire history of a batch to be traced. As a minimum, the following shall be documented:
(a)
receipt records for each delivery of materials used in the manufacture of the veterinary medicinal products including bulk products, intermediate products, and packaging materials. The receipt records shall include:
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the name of the material on the delivery note and the containers as well as any in-house name or internal code, if appropriate;
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the name of the supplier and manufacturer;
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the supplier’s batch or reference number;
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the total quantity and number of containers received;
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the date of receipt;
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the batch number assigned after receipt;
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any relevant comment;
(b)
a batch processing record which shall contain the following information:
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the name of the product and batch number;
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the dates and times of commencement, of critical intermediate stages, and of completion of production;
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the batch number or analytical control number and quantities actually weighed of each material used;
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an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person that checked these operations;
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a record of the in-process controls and the initials of the operator who carried them out;
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details of the manufacturing operations carried out and identification of major equipment used;
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the product yield obtained at relevant stages of manufacture;
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notes on any problems or unusual events that may impact on the quality of the product, including relevant details, with signed authorisation for any deviation from the manufacturing instructions;
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the approval of the batch processing record by the person responsible for the processing operations.
Where a validated process is continuously monitored and controlled, the batch record may be limited to automatically generated reports with compliance summaries and exception or out-of- specification data reports;
(c)
a batch packaging record which shall contain the following information:
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the name of the product and batch number;
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the dates and times of the packaging operations;
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an identification (e.g. by means of initials or another suitable system) of the operator who performed each significant step and, where appropriate, of the person who checked those operations;
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records of checks regarding the conformity with the packaging instructions, including the results of in-process controls;
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details of the packaging operations carried out and identification of major equipment and the packaging lines used;
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whenever possible, samples of printed packaging materials used, including the batch coding, expiry date and any additional overprinting;
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notes on any problems or unusual events that may have an impact on the quality of the product including details, with signed authorisation for any deviation from the packaging instructions;
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the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation. This information may be omitted where electronic controls are in place;
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the approval of the batch packaging record by the person responsible for the packaging operations.
2. Records shall be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of veterinary medicinal products are traceable.
3. Logbooks shall be kept for major or critical analytical testing, for production equipment and for areas where a product has been processed. They shall be used to record in chronological order, as appropriate, any use of the area, equipment or method, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried out such operations.
4. Relevant records shall form the basis for assessment of the suitability for certification and release of a particular batch.
Other documentation
1. Policies and procedures applied to safeguard the quality of the product shall be duly documented, including the following:
(a)
training;
(b)
validation of manufacturing process and relevant analytical methods;
(c)
qualification of premises and equipment (including utilities and systems);
(d)
procedures or instructions for the handling of materials and products;
(e)
release and rejection procedures for materials and products;
(f)
cleaning procedures and the validation thereof, which shall be in accordance with the requirements laid down in Annex V;
(g)
procedures relating to quality control;
(h)
maintenance and calibration of equipment;
(i)
environmental monitoring;
(j)
investigations into deviations and non-conformances;
(k)
procedures for handling of quality-related complaints and recall or return of products;
(l)
procedures for handling changes to the manufacturing process (change control);
(m)
internal audits as well as audits of suppliers and sub-contractors;
(n)
technology transfer, where applicable.
2. Clear operating procedures shall be available for main manufacturing and test equipment.
3. A site master file shall be prepared for every manufacturing site involved in the manufacture of veterinary medicinal products, which shall provide a high-level description of the premises, of the activities conducted at the manufacturing site and of the quality system implemented. A model template is set out in Annex VI.
Retention periods
1. Batch documentation shall be kept for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the qualified person, whichever is longer.
2. Critical documentation that supports information in the marketing authorisation shall be retained whilst the authorisation remains in force, including relevant raw data such as data related to validation or stability. It may be considered acceptable to retire certain documentation, such as raw data supporting validation reports or stability reports, where the data has been superseded by a full set of new data. Justification for this shall be documented and shall take into account the requirements for retention of batch documentation. In the case of process validation data, the accompanying raw data shall be retained for a period at least as long as the records for all batches whose release has been supported on the basis of that validation exercise.
3. For other types of documentation, the retention period shall depend on the business activity which the documentation supports.
Data integrity
1. Suitable measures shall be implemented to ensure data integrity from the moment when data is generated and throughout the relevant retention period, including:
(a)
implementation of measures to protect data against accidental loss or damage by appropriate methods such as duplication or back-up and transfer to another storage system;
(b)
implementation of measures to protect data against tampering or unauthorised manipulation. In the case of computerised systems, suitable controls shall be put in place to limit access to authorised persons, such as the use of keys, pass cards, personal codes with passwords, biometrics or restricted access to computer equipment and data storage areas. The type of security controls shall be adapted to the criticality of the computerised system;
(c)
implementation of measures to ensure the accuracy, completeness, availability and legibility of documents throughout the retention period. Handwritten entries shall be made in a clear, legible and indelible way.
The implemented measures shall be commensurate to the risks and the criticality of the data.
2. The issuance, revision, superseding and withdrawal of all documents shall be controlled by keeping a record of all revisions (revision histories).
3. Any alteration made to the entry on a document shall be signed and dated. The alteration shall permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
