TEMPLATE FOR THE SITE MASTER FILE
ANNEX VISupplementary provisions
ANNEX VI TEMPLATE FOR THE SITE MASTER FILE Note 1: The site master file relates to the pharmaceutical activities carried out at a specific site. If only part of a manufacturing process is undertaken at a site, the site master file need only relate to such operations (e.g. analysis, packaging). Note 2: The site master file shall contain adequate information but, as far as possible, shall not exceed 25-30 pages, plus appendices. The document shall be readable when printed on A4 paper sheets. Note 3: The site master file shall be kept up to date and be representative of current activities. The site master file shall have an edition number, the date when it becomes effective and the date by which it has to be reviewed. Each Appendix may have an individual effective date and be subject to a specific review date. 1. GENERAL INFORMATION ON THE MANUFACTURER 1.1. Contact information on the manufacturer — Name and official address of the manufacturer. — Name and street address of the site, buildings and production units located on the site. — Contact information of the manufacturer, including the telephone number of the personnel to be contacted in the case of product defects or recalls (this number shall be always operational, including outside business hours). — Identification number of the site, using a geolocalisation system such as Galileo or GPS. In addition, OMS ( 1 ) is mandatory for submissions in the EEA. 1.2. Authorised pharmaceutical manufacturing activities of the site — Copy of a valid manufacturing authorisation issued by the relevant competent authority shall be provided as Appendix 1. Alternatively, reference to the EudraGMDP database may be provided (where applicable). In cases where the relevant competent authority has not issued a manufacturing authorisation, this shall be explained. — Brief description of the manufacture, control, storage, import, export, transport or other activities authorised by the relevant competent authority(ies), including foreign authorities, with reference to the authorised pharmaceutical forms/activities, respectively, where not covered by the manufacturing authorisation. — A list with the type of products currently manufactured on-site shall be provided as Appendix 2, where not covered by Appendix 1 or EudraGMDP entry. — List of GMP inspections of the site within the last 5 years, including dates and name/country of the Competent Authority having performed the inspection. — A copy of the current GMP certificate or, alternatively, reference to the EudraGMDP database shall be provided as Appendix 3. 1.3. Any other manufacturing activities carried out on the site — Description of non-pharmaceutical activities on-site, if any. 2. QUALITY MANAGEMENT SYSTEM OF THE MANUFACTURER 2.1. The quality management system of the manufacturer — Brief description of the quality management systems run by the company and reference to the standards used. — Responsibilities related to the maintenance of the quality system, including for senior management. — Information about the activities for which the site is accredited and certified, including dates and contents of accreditations and names of the accrediting bodies. 2.2. Release procedure of finished products — Detailed description of the qualification requirements (education and work experience) of the authorised person(s) / qualified person(s) responsible for batch certification and releasing procedures. — General description of batch certification and releasing procedure. — Brief description of the batch release process, including the specific tasks of the authorised person / qualified person and arrangements for ensuring compliance with the marketing authorisation (where applicable). — The arrangements between the authorised persons / qualified persons when several authorised persons / qualified persons are involved. — Statement on whether the control strategy employs process analytical technology (PAT) or real time release or parametric release. 2.3. Management of suppliers and contractors — A brief summary of the supply chain and the external audit programme. — Brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients and other suppliers of critical materials. — Measures to ensure that products manufactured are compliant with TSE (transmissible spongiform encephalopathy) guidelines, where applicable. — Measures to address instances when counterfeit/falsified products, bulk products (i.e. unpacked tablets), active pharmaceutical ingredients or excipients are suspected or identified. — Use of outside scientific, analytical or other technical assistance in relation to the manufacture or control activities. — List of contract manufacturers and laboratories, including addresses and relevant contact information, and flow charts of supply-chains for outsourced manufacturing and quality control activities (e.g. sterilisation of primary packaging material for aseptic processes, testing of starting raw materials, etc.) shall be provided as Appendix 4. — Brief overview of the allocation of responsibilities between the contract giver and contract acceptor with respect to compliance with the marketing authorisation (where not included under 2.2). 2.4. Quality Risk Management — Brief description of the quality risk management methodologies used by the manufacturer. — Scope and focus of the quality risk management, including a brief description of any activities which are performed at corporate level and those which are performed locally. Any application of the quality risk management system to avoid disruptions of supply linked to manufacturing issues shall be mentioned. 2.5. Product Quality Reviews — Brief description of the methodologies used. 3. PERSONNEL — An organisation chart showing the arrangements for quality management, production and quality control positions/titles shall be provided as Appendix 5, including senior management and qualified person(s). — Number of employees involved in the quality management, production, quality control and storage respectively. 4. PREMISES AND EQUIPMENT 4.1. Premises — Short description of the plant, including the size of the site and list of buildings. If production for different countries takes place in different buildings on the site, the buildings shall be listed with destined markets identified (if not identified under 1.1). — Simple plan or description of the manufacturing areas with indication of the scale (architectural or engineering drawings are not required). — Layouts and flow charts of the production areas shall be provided as Appendix 6, showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms. — Layouts of warehouses and storage areas shall be provided as part of Appendix 6, with indication of special areas for the storage and handling of highly toxic, hazardous and sensitising materials, if applicable. — Brief description of specific storage conditions if applicable, unless they are already indicated on the layouts. 4.1.1. Brief description of heating, ventilation and air conditioning (HVAC) systems: — Principles for defining the air supply, temperature, humidity, pressure differentials and air change rates, policy of air recirculation (%). 4.1.2. Brief description of the water systems: — Quality references of the water produced. — Schematic drawings of the systems shall be provided as Appendix 7. 4.1.3. Brief description of other relevant utilities, such as steam, compressed air, nitrogen, etc. 4.2. Equipment 4.2.1. Listing of major production and control laboratory equipment with critical pieces of equipment identified shall be provided as Appendix 8. 4.2.2. Cleaning and sanitation: — Brief description of the cleaning and sanitation methods of product contact surfaces (i.e. manual cleaning, automatic clean-in-place, etc.). 4.2.3. GMP critical computerised systems: — Description of GMP critical computerised systems (excluding equipment specific programmable logic controllers). 5. DOCUMENTATION — Brief description of the documentation system (i.e. electronic, manual). — Where applicable, a list of the type of documents/records stored or archived off-site (including pharmacovigilance data, when applicable) shall be provided, as well as the name and address of storage site and an estimate of time required for retrieving documents from the off-site archive. 6. PRODUCTION 6.1. Type of products ( 2 ) — Type of products manufactured including a list of pharmaceutical forms. — Toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitising properties). — Product types manufactured in a dedicated facility or on a campaign basis, if applicable. — Process analytical technology (PAT) used, if applicable: general statement of the relevant technology and associated computerised systems. 6.2. Process validation — Brief description of the general policy for process validation. — Brief description of the policy for reprocessing or reworking. 6.3. Material management and warehousing — Brief description of the arrangements for the handling of materials used in the production, including packaging materials, bulk and finished products. Sampling, quarantine, release and storage shall also be addressed. — Brief description of the arrangements for the handling of rejected materials and products. 7. QUALITY CONTROL (QC) — Brief description of the quality control activities carried out on the site in terms of physical, chemical, and microbiological and biological testing. 8. TRANSPORT, COMPLAINTS, PRODUCT DEFECTS AND RECALLS 8.1. Transport arrangements (as applicable to the role of the manufacturer) — Types (wholesale licence holders, manufacturing licence holders, etc.) and locations (EU/EEA, USA, etc.) of the companies to which the products are shipped from the site. — Description of the system used to verify that each customer/recipient is legally entitled to receive the products from the manufacturer. — Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/control. — Arrangements for product distribution and methods by which product traceability is maintained. — Measures taken to prevent manufacturers’ products to fall in the illegal supply chain. 8.2. Complaints, product defects and recalls — Brief description of the system for handling complaints, product defects and recalls. 9. SELF INSPECTIONS — Brief description of the self-inspection system with a focus on the criteria used for the selection of the areas to be covered during planned inspections, practical arrangements and follow-up activities. Appendices — Appendix 1: Copy of valid manufacturing authorisation. — Appendix 2: List of pharmaceutical forms manufactured including the INN-names or common name (as available) of the active pharmaceutical ingredients (API) used. — Appendix 3: Copy of a valid GMP certificate. — Appendix 4: List of contract manufacturers and laboratories including the addresses and contact information, and flow-charts of the supply chains for these outsourced activities. — Appendix 5: Organisational charts. — Appendix 6: Layouts of production areas, including material and personnel flows and general flow charts of manufacturing processes of each product type (pharmaceutical form), and layouts of warehouse and storage areas. — Appendix 7: Schematic drawings of water systems. — Appendix 8: List of major production and laboratory equipment. ( 1 ) https://www.ema.europa.eu/en/human-regulatory-overview/research-development/data-medicines-iso-idmp-standards-overview/substance-product-organisation-referential-spor-master-data/organisation-management-service-oms . ( 2 ) Cross-reference to information provided in Appendix 1 or 2 is acceptable.