Site Master File (SMF) and Drug Master File (DMF)

A site master file (SMF) is a succinct document that provides information about the control of pharmaceutical manufacturing operations for a production site. The document is prepared by the manufacturer and contains information about the specific good manufacturing practices (GMP) operations carried out at the named site and any closely integrated operations. If only part of a pharmaceutical operation is done at the site (for example, testing, packaging), the SMF describes only those operations performed at the site.

When submitted to a regulatory authority, the SMF provides information on the manufacturer’s operations and procedures that can be useful in the efficient planning and undertaking of a GMP inspection. The GMP inspection report issued for inspections conducted by the European Medicines Agency (EMA) includes a notation on whether an SMF was available before the inspection, and the date of the SMF is included in the report.

SMFs are required by the European Union (EU), Medicines and Healthcare Products Regulatory Agency (MHRA), Pharmaceutical Inspection Convention and the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and the World Health Organization (WHO). United States Food and Drug Administration (FDA) regulations currently do not require submission or maintenance of an SMF. The mutual recognition agreements (MRA) between the European Community (EC) and Canada, New Zealand, and Australia include the SMF as part of a full inspection report that may be shared upon request.

The structure, formatting, and length of the SMF are prescribed by several guidance documents, including those published by WHO (guidelines for drafting SMF), PIC/S (explanatory notes), and the MHRA (guidance notes) (Figure 7.1). The SMF should be succinct and, where possible, not more than 25 to 30 A4 pages. For small companies, particularly those with a small product range, the SMF may be fewer than 25 pages. It is expected that the SMF will be maintained and improved to facilitate inspections.

CONTENT OF SITE MASTER FILES

Chapter 1. General Information

• Name, address, and company description (C.1.1): Includes a brief description of the company, relation to other sites, and any information relevant to understanding the manufacturing operations.
• Licensed pharmaceutical manufacturing activities (C.1.2): Provides the relevant document issued by a national authority, and, if applicable, the period of validity for the manufacturing license. This section includes any conditions/restrictions of the manufacturing license and, where applicable, the drug master file (DMF) for each product.
• Description of other pharmaceutical and nonpharmaceutical activities (C.1.3).
• Name and address of the site (C.1.4): Includes the name of the site, the complete street address and postal address, the telephone number, fax number, and e-mail address of a contact person, and a 24-hour contact telephone number.
• Products manufactured at the site (C.1.5): Lists the types of products manufactured at the site and provides information about specific toxic or hazardous substances handled, including their manufacturing. This section provides information on whether the products are manufactured in a dedicated facility or on a campaign basis and states whether both human and veterinary products are manufactured on the site. For contract manufacturing or analytical sites, this section defines whether the firm is the contract giver or acceptor.

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• Description of the site (C.1.6): Provides the location and immediate environment, and the size of the site, types of buildings, and their ages.
• Number of employees engaged in production, quality control, storage, and distribution (C.1.7): Provides the total number of employees and the number of employees engaged in production, quality control (QC), quality assurance (QA), storage and distribution, and technical and engineering support services.
• Listing and description of outside scientific, analytical, or other technical assistance in relation to manufacture and analysis (C.1.8): Provides the company name, address, telephone number, and fax number of each outside contractor, and includes a brief outline (not more than 100 words) of the activity being undertaken. Also includes the establishment license number, where applicable.
• Description of the quality management system (QMS) (C.1.9): Provides a short description (750 words or three A4 pages) of the QMS of the firm responsible for manufacture. Describes the quality policy and the responsibilities of the QA function, including audit programs, approval and starting, primary packaging material suppliers, batch release, and document control. The responsibilities specific to the head of quality, QA manager, and QC manager are included. Describes the elements of the QA system (for example, organizational structure, responsibilities, procedures, and processes, specifications, test methods, and other quality-related data collection). It is important to show that quality management is independent from production management. Briefly describes the self-inspections or audits undertaken by external organizations. A cross-reference to Chapter 9 can be added for additional details regarding the self-inspection program. Describes how quality system results are reviewed to demonstrate the adequacy of the quality system in relation to the objective. Identifies the standards used to assess or audit the company’s quality system, or used by the company to assess suppliers, such as ISO 9001, 21 CFR 211, and EU GMP. When suppliers of critical materials and packing materials are assessed, this section details how this is done, and describes the supplier selection process.

Chapter 2. Personnel

• Organization charts (C.2.1): Organization charts define the overall organizational structure for QA, production, and QC, with detailed charts for each area, depicting senior managers and supervisors only. As this information also is included in section 2.1, a cross-reference to that section can be used.
• Qualifications, experience, and responsibilities of key personnel (C.2.2): Includes brief details of academic qualifications, work-related qualifications, and years of relevant experience since qualifying.
• Training program (C.2.3): Describes how training needs are identified and by whom. Gives details of training relative to GMP requirements, including new employee training and continuous GMP training. Describes job-related skills training and in-house and external training, and how practical experience is gained. Explains how retraining needs are identified and details how training is recorded and records are maintained.

• Health requirements for production personnel (C.2.4): Describes who is responsible for checking the health of employees. Describes requirements for preemployment medical examinations and how employees are checked depending on the nature of their work. Describes the system for reporting sickness or contact with sick people before working in a critical area. Provides information on any system of reporting back to work after illness, and the requirements for personnel who work in sterile areas and any additional monitoring to which they may be subjected.
• Personnel hygiene and clothing requirements (C.2.5): States the washing, changing, and rest areas and the clothing/gowning requirements for the production areas. Gives instructions on how clothing should be used and when it should be changed. Describes gowning room/change room procedures. States the rules on eating, drinking, smoking, and use of chewing gum or tobacco. It is helpful to inspectors to include references to the applicable procedures for hygiene and clothing requirements.

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Chapter 3. Premises

• Site plan and manufacturing areas (C.3.1): Provides a site plan highlighting the production areas, and a simple plan of each production area with an indication of scale. For sterile product areas, indicates room and area classification(s) and pressure differentials between adjoining areas of different classifications.
• Nature of construction and finishes (C.3.2): A narrative format is preferred for this section. To reduce the length of the narrative for a large, complex plant, the details should be limited to critical areas, including processing and packaging areas. Describes wall construction, nature of finishes, floors, ceilings, doors and windows, lighting, piping, and drainage system(s).
• Brief description of ventilation system (C.3.3): To reduce the length of the narrative, schematic drawings should be used where possible. Details should be given for critical areas with potential risks of airborne contamination, including sterile product areas and areas for processing powders, granulation, and tableting. For manufacture of sterile or aseptic products, classification of the rooms used for production should be mentioned. A summary of the results of the most recent qualification/requalification should also be included. The MHRA guidance specifies that room classification should be given in accordance with the grading system outlined in the EC/PIC Guide to GMP. Outlines the heating, ventilation, and air conditioning (HVAC) system, areas with different classes of air, pressure differential principles to prevent cross-contamination, dedicated air handling units (AHUs), and forced ventilation systems. The limits for changing the filters should be given. If a drop-off point (DOP) is introduced, the point must be shown.
• Special areas for the handling of highly toxic, hazardous, and sensitizing materials (C.3.4): This section is similar to section C.3.1, and includes information such as whether materials are handled only in the QC laboratory, whether solids or waste are neutralized and collected in separate containers, and whether extracted gases from the fume hood are neutralized and scrubbed before they are allowed to exit into the external environment.
• Description of water and steam systems (C.3.5): This section provides a schematic drawing back to the main city supply system or source of the raw water, and the capacity of the system (maximum quantity produced per hour). Construction materials of the vessels and distribution system (pipework) are provided, along with the specification of any filters in the system. If water is stored and circulated, the temperature at the point of return is provided, and the specifications of the water produced (that is, chemical, conductivity, and microbiological descriptions) are provided. The sampling points and frequency of sampling should be included. If a steam system is needed, the same sort of information must be provided for the system.

• Description of planned preventive maintenance program and recording system (C.3.6): “Maintenance” is done by the manufacturer and “servicing” by an outside contractor. This section describes the planned preventive maintenance program, including written procedures and suitable reporting forms for maintenance and servicing.
• Brief description of major production and control laboratories equipment (C.3.7): This section provides a list of equipment. Although the make and model numbers of the equipment are not required, several points should be addressed, including appropriateness and validity of construction material and ease of cleaning. For specific pieces of machinery (for example, a rotary tablet press), only a general description is required. If the equipment has additional devices, however, these devices should be recorded (for example, automatic weighing machines with printer, a labeler incorporating a bar code reader for the label). Further information is required for QC laboratory and microbiology laboratory and for computers and microprocessors in the manufacturing facility.
• Maintenance (description of planned preventive maintenance program and recording system) (C.3.8): Identifies who is responsible for maintenance and servicing and whether there are written procedures and contractual details for servicing. Maintenance routines that could affect product quality must be identified, and annual planned preventive maintenance programs for equipment must be in accordance with machine/instrument manufacturers’ requirements. Documentation must be provided that records are kept on the type and frequency of service or check, details of service repairs and modifications, and reports provided to the users.
• Qualification, validation, and calibration, including recording system and arrangements for computerized systems validation (C.3.9): This section briefly describes the company’s general policy and protocols for qualification, prospective validation, and retrospective validation, and describes and outlines the essential steps of the manufacturing process validation and cleaning validation. Any revalidation policy must be described. An outline of process validation may be given here or cross-referenced to production paragraph 5.4. A description of the system for the release for sale or supply of development and validation batches should be provided, as well as the arrangements for computer validation, including software validation. The equipment calibration policy and how calibration records are kept should be included in this section.
• Availability of written specifications and procedures for cleaning manufacturing areas and equipment (C.3.10): This section summarizes the cleaning strategy, schedules, and documentation for manufacturing areas and equipment. If cleaning agents are changed periodically, it should be noted, along with any validation of cleaning processes, including the cleaning methods (and their frequency) for the water supply system, air handling system, and dust extraction system.

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