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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.
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.
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.
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.
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.
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.
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Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.