1.0 Introduction
Pharmaceutical manufacturer prepares the site master file specifying the information about quality management activities & policies of the site, QC or production operations done at site and any integrated operations at nearby buildings. When operations like packaging, analysis are carried out then only operations which are carried out should be described in SMF.
When SMF is submitted to regulatory authority it should provide information on manufacturers GMP related activities which are useful in planning, undertaking and supervision of GMP inspection
SMF should provide information with not exceeding 25-30pages in addition to appendices.
Simple plans with drawings and layouts are preferred to narratives. They should be readable when printed in A4 format paper sheets.
SMF is a part of documentation under quality management system and it should be updated by the manufacturer regularly. The SMF should include edition number, date from which it is effective and the date it needs to be reviewed. Periodical review should ensure that information should be of current status & activities. Every annex should have effective date with ease to update it independently.
1.1 Purpose
The guidelines are given to the manufacturer to prepare SMF in compliance with the regulatory authority of planning in conducting GMP inspections
1.3 Scope
The explanatory notes are applicable in preparing the content for SMF. Manufacturers should prepare the SMF in compliance with national regulatory requirements and check if it is necessary to prepare to SMF for the given medicinal products.
The explanatory notes given apply for all manufacturing operations like production, testing, packaging, labeling, relabeling & repackaging of medicinal products.
2.0 Contents of SMF
2.1 General – Manufacturer
a) Contact information of manufacturer
- Manufacturers name & official address
- Name & address of site, building, production units on site
- Manufacturers contact information with telephone number on which the manufacture is available 24 hours or at any time in case of product recall or defect
- Site identification number with details of global positioning system (GPS), Data Universal Numbering System – DUNS number (unique number given by Dun & Bradstreet) for the site with any other available geographical location system
b) Authorized manufacturing activities of the site
- A copy of valid manufacturing authorization given by the authority in annex 1 and if applicable reference to EudraGMP database can be given
- If the authority does not issue manufacturing authorizations then the following should be stated:
- Description of activities like manufacturing, distribution, export, import and other activities which are authorized by competent authorities and foreign authorities who are not covered under manufacturing authorization
- Product types which are manufactured on site which are listed in annex 2 but not covered under annex 1 or EudraGMP database
- List of inspections conducted by GMP in the last 5 years with their dates, name or country of the authority who conducts the inspection
- A copy of the GMP certificate or a reference to EudraGMP database should be included
c) Other manufacturing activities on the site
- Description of non-pharmaceutical activities on the site
3.0 Quality management
3.1 Quality management by the manufacturer
- Description of the manufacturing system by the company and the standard references
- Responsibilities of the senior management in the maintenance of quality system
- Information on site accreditation and certification and their dates & contents and names of accredited bodies
3.2 Procedure for release of finished products
- Details of the qualification of qualified or authorized persons for certification of batch & procedures for releasing
- Description of certification of batch & procedures for releasing
- Role of authorized person in quarantine & finished products and assessing them in compliance with marketing authorization
- Statement should be produced whether control strategy involves process analytical technology and parametric or real time release
- When many authorized persons are involved then proper arrangements should be made between them
3.3 Management of suppliers & contractors
- Knowledge of external audit programme & supply chain
- Description of qualification of manufacturers, contractors of APIs & other suppliers of critical materials
- To ensure that the products manufactured are in compliance with transmitting animal spongiform encephalopathy guidance proper measures to be taken
- Proper measures should be taken in identifying or suspecting spurious or falsified or substandard or falsely labeled or counterfeit products or unpacked tablets, APIs and excipients
- Scientific, technical or analytical assistance should be used in relation to analysis & manufacture
- List of the laboratories, contract manufacturers along with their contact information, address, flowcharts of supply chain for outsourced QC activities & manufacturing should be given in annex 4
- Overview of the role & responsibilities shared by contract giver and acceptor in compliance to the market authorization
3.4 Quality Risk Management
- Description of methodologies of quality risk management which are used by the manufacturer
- Scope and focus of quality risk management should include description of various activities performed at corporate level as well the activities that are performed locally
- If the QRM system helps in maintaining a continuous supply then it should be mentioned
3.5 Product quality reviews
- Description of the methodologies of various product quality reviews
4.0 Personnel
- An organizational chart showing arrangements for quality management, quality control and various positions in production should be given in Annex 5 and senior management & authorized persons should also be included
- It should also include the number of employees who are engaged in quality management, quality control, production, storage, distribution
5.0 Premises
- A brief description should be given describing the plant size and list of the buildings. If production for different countries or markets takes place in different buildings then they should be listed with the destined markets
- Description or a simple plan for the manufacturing areas should be given with the scale indication
- Production areas layout design & flowchart with classification of rooms and pressure differentials and the production activities should be indicated like filling, compounding, storage and packaging in the room
- Warehouses and storage areas layout with areas for handling and storage of hazardous, sensitizing & highly toxic materials should be indicated
- Storage conditions description should be given
5.1 HVAC systems
- Principles should regarding the usage of air supply, air recirculation policy, air change rates, humidity, pressure differentials and temperature
5.2 Water system
- Quality reference of the water that is produced
- Drawings of the systems should be given in Annex 7
5.3 Others
- A brief description of the utilities like nitrogen, compressed air and steam should be given
6.0Equipment
- List of the major equipment used in production and laboratory along with critical pieces of equipment should be given in Annex 8
6.1 Cleaning & Sanitation
- Description of the methods of sanitation & cleaning for the surfaces in contact with product (automatic clean in place, manual cleaning)
6.2 Computerized systems
- Description of the GMP critical computerized systems should be given excluding programmable logic controllers which are specific to equipment’s
7.0 Documentation
- Description should be given on the type of documentation whether it is electronic or manual documentation
- When the records or documents are stored then list of the various records or documents with their name & address of the storage site along with time estimation for documents retrieval from the off – site archive should be given
8.0 Production
8.1 Product types
Various kinds of products that are manufactured should include
- Dosage forms list for both veterinary and human products that are manufactured on the site
- Dosage forms list for Investigational Medicinal Products (IMP) manufactured for the clinical trials which are done on the site.
- When the manufacturing is different from commercial manufacturing then the information should be given regarding their production areas & personnel
- Description of the hazardous or toxic substances with their pharmacological activity & sensitizing properties
- Description of the various products that are manufactured on campaign basis or in dedicated facility
- Applications of PAT and any general statement of relevant technology with their associated computerized systems
8.2 Process validation
- Description of the policy for process validation
- Description of the policies for reworking or reprocessing
8.3 Warehouse – Material Management
- Description on the arrangement for handling starting materials, finished goods, packaging materials along with processes like sampling, release, storage and quarantine
- Description on the arrangement for handling rejected products and materials
9.0 Quality control
- Description of various QC activities which are done on the site in terms of biological, microbiological, chemical and physical testing
10.0 Distribution
Distribution activities are under the responsibility of the manufacturer
- Description of various type of license holders like manufacturing & wholesale license holders with their locations in various countries or economic areas of the companies to where the products are shipped from site
- Description of the system where every customer is verified whether he is legally entitled to receive the medicinal products from manufacturer
- Description of the system should be given regarding environmental conditions like temperature control and monitoring during transportation
- Product distribution arrangements and methods through which product can be traced easily
- Description of measures taken to safeguard the products from entering into illegal supply chain
10.1 Complaints & recalls
- Description of the system for solving complaints, product defects & recalls
10.3 Self-inspection
Description of self-inspection system focusing on the criteria for selecting areas which are to be covered in planned inspections, follow up activities & practical arrangements
Annexes in submission of SMF
Annex 1 – Copy of valid manufacturing authorization
Annex 2 – list of dosage forms manufactured including the International nonproprietary names (INN) or common name of APIs used
Annex 3 – Copy of valid GMP certificate
Annex 4 – list of contract manufacturers and laboratories including the addresses and contact information and flowcharts of the supply chains for these outsourced activities
Annex 5 – Organizational charts
Annex 6 – layouts of production areas including material and personnel flows, general flowcharts of manufacturing processes of each product type (dosage form)
Annex 7 – Schematic drawings of water systems
Annex 8 – list of major production and laboratory equipment
