EU-GDP

II (Information) INFORMATION FROM EUROPEAN UNION INSTITUTIONS, BODIES, OFFICES AND AGENCIES OTHER ACTS Guidelines of 7 March 2013 on Good Distribution Practice of Medicinal Products for Human Use (2013/C 68/01) INTRODUCTION These guidelines are based on Article 84 and Article 85(b)(3) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use ( 1 ) (Directive 2001/83/EC). The wholesale distribution of medicinal products is an important activity in integrated supply chain management. Today’s distribution network for medicinal products is increasingly complex and involves many players. These guidelines lay down appropriate tools to assist wholesale distributors in conducting their activities and to prevent falsified medicines from entering the legal supply chain. Compliance with these guidelines will ensure control of the distribution chain and consequently maintain the quality and the integrity of medicinal products. According to Article 1(17) of Directive 2001/83/EC, wholesale distribution of medicinal products is all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their depos­ itories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned. Any person acting as a wholesale distributor has to hold a wholesale distribution authorisation. Article 80(g) of Directive 2001/83/EC provides that distributors must comply with the principles of and guidelines for good distribution practice (GDP). Possession of a manufacturing authorisation includes author­ isation to distribute the medicinal products covered by the au­ thorisation. Manufacturers performing any distribution activities with their own products must therefore comply with GDP. The definition of wholesale distribution does not depend on whether that distributor is established or operating in specific customs areas, such as in free zones or in free warehouses. All obligations related to wholesale distribution activities (such as exporting, holding or supplying) also apply to these distributors. Relevant sections of these guidelines should also be adhered to by other actors involved in the distribution of medicinal products. Other actors such as brokers may also play a role in the distribution channel for medicinal products. According to Article 85(b), persons brokering medicinal products must be subject to certain provisions applicable to wholesale distributors, as well as specific provisions on brokering. CHAPTER 1 — QUALITY MANAGEMENT 1.1. Principle Wholesale distributors must maintain a quality system setting out responsibilities, processes and risk management principles in relation to their activities ( 2 ). All distribution activities should be clearly defined and systematically reviewed. All critical steps of distribution processes and significant changes should be justified and where relevant validated. The quality system is the responsibility of the organisation’s management and requires their leadership and active participation and should be supported by staff commitment. EN 8.3.2013 Official Journal of the European Union C 68/1 ( 1 ) OJ L 311, 28.11.2001, p. 67. ( 2 ) Article 80(h) of Directive 2001/83/EC. 1.2. Quality system The system for managing quality should encompass the organ­ isational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the product delivered maintains its quality and integrity and remains within the legal supply chain during storage and/or transportation. The quality system should be fully documented and its effecti­ veness monitored. All quality system-related activities should be defined and documented. A quality manual or equivalent docu­ mentation approach should be established. A responsible person should be appointed by the management, who should have clearly specified authority and responsibility for ensuring that a quality system is implemented and maintained. The management of the distributor should ensure that all parts of the quality system are adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. The size, structure and complexity of distributor’s activities should be taken into consideration when developing or modifying the quality system. A change control system should be in place. This system should incorporate quality risk management principles, and be proportionate and effective. The quality system should ensure that: (i) medicinal products are procured, held, supplied or exported in a way that is compliant with the requirements of GDP; (ii) management responsibilities are clearly specified; (iii) products are delivered to the right recipients within a satisfactory time period; (iv) records are made contemporaneously; (v) deviations from established procedures are documented and investigated; (vi) appropriate corrective and preventive actions (commonly known as CAPA) are taken to correct deviations and prevent them in line with the principles of quality risk management. 1.3. Management of outsourced activities The quality system should extend to the control and review of any outsourced activities related to the procurement, holding, supply or export of medicinal products. These processes should incorporate quality risk management and include: (i) assessing the suitability and competence of the Contract Acceptor to carry out the activity and checking authorisation status, if required; (ii) defining the responsibilities and communication processes for the quality-related activities of the parties involved; (iii) monitoring and review of the performance of the Contract Acceptor, and the identification and implementation of any required improvements on a regular basis. 1.4. Management review and monitoring The management should have a formal process for reviewing the quality system on a periodic basis. The review should include: (i) measurement of the achievement of quality system objectives; (ii) assessment of performance indicators that can be used to monitor the effectiveness of processes within the quality system, such as complaints, deviations, CAPA, changes to processes; feedback on outsourced activities; self-assessment processes including risk assessments and audits; and external assessments such as inspections, findings and customer audits; (iii) emerging regulations, guidance and quality issues that can impact the quality management system; (iv) innovations that might enhance the quality system; (v) changes in business environment and objectives. The outcome of each management review of the quality system should be documented in a timely manner and effectively communicated internally. 1.5. Quality risk management Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of medicinal products. It can be applied both proactively and retrospectively. EN C 68/2 Official Journal of the European Union 8.3.2013 Quality risk management should ensure that the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient. The level of effort, formality and documentation of the process should be commensurate with the level of risk. Examples of the processes and applications of quality risk management can be found in guideline Q9 of the International Conference on Harmonisation (ICH). CHAPTER 2 — PERSONNEL 2.1. Principle The correct distribution of medicinal products relies upon people. For this reason, there must be sufficient competent personnel to carry out all the tasks for which the wholesale distributor is responsible. Individual responsibilities should be clearly understood by the staff and be recorded. 2.2. Responsible person The wholesale distributor must designate a person as Responsible Person. The Responsible Person should meet the qualifications and all conditions provided for by the legislation of the Member State concerned ( 1 ). A degree in pharmacy is desirable. The Responsible Person should have appropriate competence and experience as well as knowledge of and training in GDP. The Responsible Person should fulfil their responsibilities personally and should be continuously contactable. The Responsible Person may delegate duties but not responsibilities. The written job description of the Responsible Person should define their authority to take decisions with regard to their responsibilities. The wholesale distributor should give the Responsible Person the defined authority, resources and responsibility needed to fulfil their duties. The Responsible Person should carry out their duties in such a way as to ensure that the wholesale distributor can demonstrate GDP compliance and that public service obligations are met. The responsibilities of the Responsible Person include: (i) ensuring that a quality management system is implemented and maintained; (ii) focusing on the management of authorised activities and the accuracy and quality of records; (iii) ensuring that initial and continuous training programmes are implemented and maintained; (iv) coordinating and promptly performing any recall operations for medicinal products; (v) ensuring that relevant customer complaints are dealt with effectively; (vi) ensuring that suppliers and customers are approved; (vii) approving any subcontracted activities which may impact on GDP; (viii) ensuring that self-inspections are performed at appropriate regular intervals following a prearranged programme and necessary corrective measures are put in place; (ix) keeping appropriate records of any delegated duties; (x) deciding on the final disposition of returned, rejected, recalled or falsified products; (xi) approving any returns to saleable stock; (xii) ensuring that any additional requirements imposed on certain products by national law are adhered to ( 2 ). 2.3. Other personnel There should be an adequate number of competent personnel involved in all stages of the wholesale distribution activities of medicinal products. The number of personnel required will depend on the volume and scope of activities. The organisational structure of the wholesale distributor should be set out in an organisation chart. The role, responsibilities, and interrelationships of all personnel should be clearly indicated. The role and responsibilities of employees working in key positions should be set out in written job descriptions, along with any arrangements for deputising. 2.4. Training All personnel involved in wholesale distribution activities should be trained on the requirements of GDP. They should have the appropriate competence and experience prior to commencing their tasks. Personnel should receive initial and continuing training relevant to their role, based on written procedures and in accordance with a written training programme. The Responsible Person should also maintain their competence in GDP through regular training. EN 8.3.2013 Official Journal of the European Union C 68/3 ( 1 ) Article 79(b) of Directive 2001/83/EC. ( 2 ) Article 83 of Directive 2001/83/EC. In addition, training should include aspects of product identifi­ cation and avoidance of falsified medicines entering the supply chain. Personnel dealing with any products which require more stringent handling conditions should receive specific training. Examples of such products include hazardous products, radio­ active materials, products presenting special risks of abuse (including narcotic and psychotropic substances), and temperature-sensitive products. A record of all training should be kept, and the effectiveness of training should be periodically assessed and documented. 2.5. Hygiene Appropriate procedures relating to personnel hygiene, relevant to the activities being carried out, should be established and observed. Such procedures should cover health, hygiene and clothing. CHAPTER 3 — PREMISES AND EQUIPMENT 3.1. Principle Wholesale distributors must have suitable and adequate premises, installations and equipment ( 1 ), so as to ensure proper storage and distribution of medicinal products. In particular, the premises should be clean, dry and maintained within acceptable temperature limits. 3.2. Premises The premises should be designed or adapted to ensure that the required storage conditions are maintained. They should be suitably secure, structurally sound and of sufficient capacity to allow safe storage and handling of the medicinal products. Storage areas should be provided with adequate lighting to enable all operations to be carried out accurately and safely. Where premises are not directly operated by the wholesale distributor, a contract should be in place. The contracted premises should be covered by a separate wholesale distribution authorisation. Medicinal products should be stored in segregated areas which are clearly marked and have access restricted to authorised personnel. Any system replacing physical segregation, such as electronic segregation based on a computerised system, should provide equivalent security and should be validated. Products pending a decision as to their disposition or products that have been removed from saleable stock should be segregated either physically or through an equivalent electronic system. This includes, for example, any product suspected of falsification and returned products. Medicinal products received from a third country but not intended for the Union market should also be physically segregated. Any falsified medicinal products, expired products, recalled products and rejected products found in the supply chain should be immediately physically segregated and stored in a dedicated area away from all other medicinal products. The appropriate degree of security should be applied in these areas to ensure that such items remain separate from saleable stock. These areas should be clearly identified. Special attention should be paid to the storage of products with specific handling instructions as specified in national law. Special storage conditions (and special authorisations) may be required for such products (e.g. narcotics and psychotropic substances). Radioactive materials and other hazardous products, as well as products presenting special safety risks of fire or explosion (e.g. medicinal gases, combustibles, flammable liquids and solids), should be stored in one or more dedicated areas subject to local legislation and appropriate safety and security measures. Receiving and dispatch bays should protect products from prevailing weather conditions. There should be adequate separation between the receipt and dispatch and storage areas. Procedures should be in place to maintain control of inbound/ outbound goods. Reception areas where deliveries are examined following receipt should be designated and suitably equipped. Unauthorised access to all areas of the authorised premises should be prevented. Prevention measures would usually include a monitored intruder alarm system and appropriate access control. Visitors should be accompanied. Premises and storage facilities should be clean and free from litter and dust. Cleaning programmes, instructions and records should be in place. Appropriate cleaning equipment and cleaning agents should be chosen and used so as not to present a source of contamination. Premises should be designed and equipped so as to afford protection against the entry of insects, rodents or other animals. A preventive pest control programme should be in place. Rest, wash and refreshment rooms for employees should be adequately separated from the storage areas. The presence of food, drink, smoking material or medicinal products for personal use should be prohibited in the storage areas. EN C 68/4 Official Journal of the European Union 8.3.2013 ( 1 ) Article 79(a) of Directive 2001/83/EC. 3.2.1. Temperature and environment control Suitable equipment and procedures should be in place to check the environment where medicinal products are stored. Environ­ mental factors to be considered include temperature, light, humidity and cleanliness of the premises. An initial temperature mapping exercise should be carried out on the storage area before use, under representative conditions. Temperature monitoring equipment should be located according to the results of the mapping exercise, ensuring that monitoring devices are positioned in the areas that experience the extremes of fluctuations. The mapping exercise should be repeated according to the results of a risk assessment exercise or whenever significant modifications are made to the facility or the temperature controlling equipment. For small premises of a few square meters which are at room temperature, an assessment of potential risks (e.g. heaters) should be conducted and temperature monitors placed accordingly. 3.3. Equipment All equipment impacting on storage and distribution of medicinal products should be designed, located and maintained to a standard which suits its intended purpose. Planned main­ tenance should be in place for key equipment vital to the functionality of the operation. Equipment used to control or to monitor the environment where the medicinal products are stored should be calibrated at defined intervals based on a risk and reliability assessment. Calibration of equipment should be traceable to a national or international measurement standard. Appropriate alarm systems should be in place to provide alerts when there are excursions from predefined storage conditions. Alarm levels should be appropriately set and alarms should be regularly tested to ensure adequate functionality. Equipment repair, maintenance and calibration operations should be carried out in such a way that the integrity of the medicinal products is not compromised. Adequate records of repair, maintenance and calibration activities for key equipment should be made and the results should be retained. Key equipment would include for example cold stores, monitored intruder alarm and access control systems, refrigerators, thermo hygrometers, or other temperature and humidity recording devices, air handling units and any equipment used in conjunction with the onward supply chain. 3.3.1. Computerised systems Before a computerised system is brought into use, it should be demonstrated, through appropriate validation or verification studies, that the system is capable of achieving the desired results accurately, consistently and reproducibly. A written, detailed description of the system should be available (including diagrams where appropriate). This should be kept up to date. The document should describe principles, objectives, security measures, system scope and main features, how the computerised system is used and the way it interacts with other systems. Data should only be entered into the computerised system or amended by persons authorised to do so. Data should be secured by physical or electronic means and protected against accidental or unauthorised modifications. Stored data should be checked periodically for accessibility. Data should be protected by backing up at regular intervals. Backup data should be retained for