Standard Operating Procedure (SOP) and Guideline for preparation, approval, and revision of Site Master File (SMF). The Site Master File (SMF) Document shall contain specific information about the quality management policies, activities of the site, the production and/or quality control, pharmaceutical manufacturing operations, and any closely integrated operations at adjacent and nearby buildings.
Guideline for Preparation of Site Master File (SMF)
The purpose of this SOP is to provide the procedure for preparation, approval, and revision of Site Master File (SMF) at the pharmaceutical drug manufacturing site.
The Site Master File (SMF) Document shall contain specific information about the
Quality management policies,
Activities of the site,
Pharmaceutical Manufacturing Operations, and
Any closely integrated operations at adjacent and nearby buildings.
If only part of a pharmaceutical operation is performed on-site, a Site Master File (SMF) shall only describe those specific operations (i.e., analysis, packaging, etc.).
SITE MASTER FILE (SMF):
CCR: Change Control Record
cGMP: Current Good Manufacturing Practices
SMF: Site Master File
A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous, to have uniform composition, character, and quality within specified limits, and is produced according to a master manufacturing order.
Any product that has completed all processing stages up to, but not including, final packaging.
API –Active Pharmaceutical Ingredient:
An ingredient intended to furnish pharmacologic activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body; it does not include intermediates used in the synthesis of such an ingredient.
Corrective Action/Preventive Action:
A concept with current Good Manufacturing Practice (cGMP) that focuses on the systematic investigation of root causes of unexpected incidences to prevent their recurrence (corrective action) or to prevent their occurrence (preventive action). (SOP for CAPA)
Action is taken to eliminate the causes of an existing nonconformity, defect, or other undesirable situation, in order to prevent a recurrence.
Action is taken to eliminate the cause of a potential nonconformity, defect, or other undesirable situation, in order to prevent occurrence.
cGxP is a general term that stands for current Good “x” Practice (x = Clinical, Engineering, Laboratory, Manufacturing, Documentation, Pharmaceutical, etc.).
The titles of these Good “x” Practice guidelines usually begin with “Good” and end in “Practice”. cGxP represents the abbreviations of these titles where “x” a common symbol for a variable, represents the specific descriptor.
A formal procedure for proposing, assessing, documenting, and approving changes that could affect the safety, purity, quality, or identity of the product, or could affect the validation of a process or testing methods.
A finished dosage form, for example, tablet, capsule, solution, etc., that contains an Active Pharmaceutical Ingredient(s) (API) generally, but not necessarily in association with inactive ingredients.
The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo.
A device that operates either as a ‘stand-alone’ or combines several instruments or pieces of equipment to give an output.
The equipment performs a unit operation or many unit operations.
A system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release.
Quality Risk Management:
Quality Risk Management is a systematic process for the assessment, control, communication, and review of risks to the quality of drug products across the product lifecycle. (SOP for Quality Risk Management)
Site Master File (SMF) :
A document in the pharmaceutical industry, which provides information about the production and control of manufacturing operations.
The document is created by a manufacturer.
Validation Establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.
6.0 PROCEDURE FOR PREPARATION OF SITE MASTER FILE (SMF):
Site Master File (SMF) Key Elements:
General Information of the Manufacturer
Quality Management System of the Manufacturer
Premises (Facility) and Equipment
Quality Control (QC)
Distribution, Complaints, Product Defects, and Recalls
List of GMP inspections of the site within the last 5 years
Site master file (SMF) appendix shall include the following information/documentation:
Copy of Valid Manufacturing Authorization…………………………………………..Appendix 1
Copy of Valid GMP Certificate………………………………………………………………Appendix 2
List of dosage forms and molecules manufactured including the INN-names or common name (as available) of Active Pharmaceutical Ingredients (API) used…………………….. Appendix 3
Layouts of Production area (Man & Material movement)…………………………Appendix 4
Contract Agreement, 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
List of Key Personnel……………………………………………………………………………Appendix 7
Schematic drawings of the water system(s)…………………………………………….Appendix 8
List of Major Production and Laboratory Equipment………………………………Appendix 9
List of AHU with serving area……………………………………………………………….Appendix 10
Flow chart of Tablet, Capsule, Bottle filling, and sachet……………………………Appendix 11
What is the Site Master File (SMF)?
The document prepared by the manufacturer, containing specific and factual Good Manufacturing practices (GMP) information about the production and the control of pharmaceutical products at the site.
The Site Master File (SMF) shall provide clear information regarding GMP related activities that can be useful in the general supervision and in the efficient planning and undertaking of GMP inspections.
Contain adequate information but not to exceed 25-30 pages plus appendices.
Simple plans outline drawings, or schematic layouts, are preferred instead of narratives.
The Site Master File (SMF), including appendices, shall be readable when printed on A4 paper sheets.
When submitted to a regulatory authority, the Site Master File (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 SMF shall be prepared/reviewed once a year, preferably in the month of January of every year.
The Site Master File (SMF) shall be part of documentation belonging to the Quality Management System and updated accordingly when necessary.
The numbering System for Site Master File (SMF) shall be as follows:
XX- stands for short name of company/site
SMF- stands for Site Master File
YYYY: Current Year (e.g. 2020)
ZZ- stands for Revision number in ascending order starting with 00
Any modifications thereafter shall be addressed as amendments to the SMF & reference change control details to be mentioned in the revision history.
Any modification in the annexures shall be revised separately, no need to revise SMF.
As and when SMF is revised, accordingly Annexures No. shall be revised with 00 revision suffix to the current revision no. of SMF.
Wherever possible, simple plans, outline drawings, or schematic layouts shall be used instead of narrative.
The Site Master File (SMF) shall be prepared by QA Head, Approved by the Quality head and Plant Head.
Each section of the SMF shall start on a new page.
The first approval page of the Site Master File (SMF) shall be signed by the QA head, Head-Quality, and Plant Head.
First Page of the Site Master File (SMF) shall contain the following headings:
Name and Address of Site
Title: Site Master File (SMF)
Document Number, i.e. XX/SMF/YYYY/ZZ
Effective Date and Next Review Date.
A separate index shall be prepared for Annexures and Amendment(s) as per Annexure-2 & Annexure-3 respectively.
The amendment can be in the form of printed formats, layouts, handwritten information, etc.
The Site Master File (SMF) shall be prepared on A4 paper using the following parameters:
A4 paper (210 X 297 mm)
Header & Footer
Header : 0.8” Footer : 0.5”
White paper with Company Logo
<Company Name> Font: Times New Roman, Font Style: Bold, Font Size: 14, Alignment: Center
Manual Sub Heading
Font: Times New Roman, Font Style: Bold Font Size: 12, Alignment: Center
Page X of Y
* Adjust the header/footer in such a manner that the logo is not covered by Header text.
The Site Master File (SMF) shall be prepared with the following headings and details in the header.
<Company Name> <Company Address>
Site Master File (SMF)
Next Review Date:
Document No.: This is the unique alphanumeric identification number allotted to the Site Master File (SMF).
Section: This shall be the serial number of that particular section. (Refer point no.)
Supersedes: In case of revision of SMF, mention the SMF No. of the superseded SMF. In the case of new SMF, mention “NA”.
Issue Date: The date on which the Site Master File (SMF) is approved by Quality Head, the same date shall be handwritten on all respective pages. The date format shall be DD/MM/YY.
Effective date: The date on which the Site Master File (SMF) is approved by Factory Head, the same date shall be handwritten on all respective pages. The date format shall be DD/MM/YY.
Next Review Date: Next Review date is the date before which the Site Master File (SMF) shall be reviewed. The date shall be handwritten in DD/MM/YY format.
The Next review date shall be one year from the effective date, which shall be handwritten on all respective pages.
Title: This shall include the headings for that particular section.
The footer for Site Master File (SMF) shall include page numbering in the form of Page X of Y, where X is the page number and Y is the total number of pages of Site Master File (SMF).
The Site Master File (SMF) shall have the index page with the following details but not limited to :
Name and Address of Site
Other Manufacturing Activity at Site
Types of Product Manufactured
Description of the Site
Employment at Site
Use of Out Side Technical Services
Quality Management System
Release Procedure of Finished Products includes the following
Management of Suppliers and Contractors
Quality Risk management
Annual Quality review
Key Personnel (Qualifications, Experience, and Responsibilities)
Health Requirements for personnel engaged in manufacturing activity.
Personnel Hygiene Requirement Including Clothing
Premises & Equipment
Description of Manufacturing Areas (Man and Material Movement)
Nature of Construction and Finishes
Design Criteria For Ventilation Systems Schematic Diagram For HVAC and Dust Extraction System
Special Area for the handling of highly toxic, hazardous, and sensitizing materials
Brief Description of Water System and Other Utilities
Planned Preventive Maintenance for Premises and utilities
Description of Major Equipment for Production, Quality Control Laboratory & Engineering Equipment
Planned Preventive Maintenance for Equipment
Qualification, Validation, and Calibration
Cleaning and Sanitation.
GMP Critical computerized systems
Preparation, revision, and distribution of necessary documentation for manufacturing
Other documentation related to product quality
Brief description of production operation
Arrangement for the handling of starting material, packaging material, bulk and finished product including sampling, quarantine, release, and storage
A brief description of the arrangement for the handling of rejected materials and products
Brief description of general policy for process validation
Describe Policy for Reprocessing or Reworking
Description of the Quality Control System and of the activities of the Quality Control Department & Procedures for the release of finished products
Distribution, Product Defect, Complaint, and Product Recall
Description of Storage and Distribution Practices
Handling of Product Defects, Complaints, and Product Recall
Description of Self Inspection Program
List of Annexures
A separate index for Amendment
C1 – General Information – Site Master File (SMF):
This shall include brief information about the organization, other sites, and information regarding the manufacturing activities at the company.
C1.2 – Name and Address of Site:
Name, and official address of the company’s manufacturing site contact person (s).
Names, and street addresses of the site, buildings, and production units located on the site.
Contact information for the manufacturing site, including twenty-four (24) hour telephone number, email address of the contact person in the case of product defects or recalls.
Identification number of the manufacturing site such as Global Positioning System (GPS) details, or any other geographic location system,
D-U-N-S (Data Universal Numbering System) Number (a unique identification number provided by Dun & Bradstreet) of the site and/or Facility Establishment Identifier (FEI), a unique identifier designated by FDA.
C1.3 – Manufacturing Activities – Site Master File (SMF):
Authorized pharmaceutical manufacturing activities at the site include the following:
Copy of the valid manufacturing authorization issued by the relevant Competent Authority in Appendix 1.
If the Competent Authority does not issue manufacturing authorization, this shall be stated in the document.
A brief description of manufacture, import, export, distribution, and other activities as authorized by the relevant Competent Authorities including foreign authorities with authorized dosage forms/activities, respectively; were not covered by the manufacturing authorization.
The type of products currently manufactured on-site (list in Appendix 2) was not covered by Appendix 1.
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 (Appendix 3) or other relevant references shall be included, if available.
A brief description of Pharmaceutical manufacturing activities as licensed by the national authority.
This shall also include the validity period for the manufacturing license issued by the national regulatory authority.
C1.4 – Other Manufacturing Activity at Site.
This covers both pharmaceutical and non-pharmaceutical activities.
C1.5 – Types of Products Manufactured – Site Master File (SMF):
Type of actual products manufactured on the site and information about specifically toxic or hazardous substances handled, mentioning the way they are manufactured (in dedicated facilities or on a campaign basis). Product list to be attached as an annexure.
C1.6 – Description of the Site:(NMT 250 words/one A4 page)
A short description of the site shall be explained under this clause.
These shall include information about the location, immediate environment, area covered by the site, building facility details, size of the site, type of buildings, and their
C1.7 – Employment at Site:
The detailed information about the total number of employees engaged in the site shall be provided.
This shall include any part-time employees also.
The categorization of employees shall be done as mentioned below but not limited to:
Storage & Distribution
Technical & Engineering services
Total of above
Note: Include employees working only part-time on a full-time equivalent basis.
C1.8 – Use of Out Side Technical Services:
Detail of use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis shall be mentioned along with the name, address, telephone number, fax no, and brief outline of the activity being undertaken. (NMT 100 words/half an A4 page)
Scope and focus of QRM including a brief description of any activities which are performed at the corporate level, and those which are performed locally.
Any application of the QRM system to assess continuity of supply should be mentioned.
Short description of Quality by Design(QbD) and Continued Process Verification(CPV).
A short description of the control strategy employs process analytical technologies (PAT).
C2.1 – Release Procedure for Finished Products includes the following:
Provide a detailed description of qualification requirements, (education and work experience) of the Authorized Person(s) / Qualified Person(s) responsible for batch certification and release procedures.
Provide a general description of batch certification and releasing procedure.
Describe the role of Authorized Person/Qualified Person regarding quarantine, and release of finished products, and assessment of compliance with the Marketing Authorization.
Describe the arrangements and roles between Authorized Persons/Qualified Persons when several Authorized Persons/Qualified Persons are involved.
Provide a statement on whether the control strategy employs Process Analytical Technology (PAT) and/or Real-Time Release or Parametric Release.
C2.2 – Management of Suppliers and Contractors – Site Master File (SMF):
Provide a brief summary of the establishment/ knowledge of the supply chain and the external audit program.
Provide a brief description of the qualification system of contractors, manufacturers of active pharmaceutical ingredients (API), and other critical materials suppliers.
Describe the procedure(s) in use to ensure that products manufactured are compliant with TSE (Transmitting animal spongiform encephalopathy) guidelines.
Procedure(s) in use when substandard, counterfeit/ falsified products, bulk products (i.e. unpacked tablets), active pharmaceutical ingredients, or excipients, which are suspected or identified.
Describe when the site utilizes outside scientific, analytical, or other technical assistance, in relationship to manufacture of product and analysis.
Provide a listing of all contract manufacturers, and laboratories, including the addresses and contact information.
Provide flow charts of supply-chains for outsourced manufacturing and Quality Control activities i.e.
Sterilization of primary packaging material for aseptic processes,
The testing of starting raw materials, etc., shall be presented in Appendix 4).
Provide a brief overview of the responsibility-sharing between the contract giver and acceptor with respect to compliance with the Marketing Authorization.
C2.3 – Quality Risk Management (QRM):
Provide a brief description of QRM methodologies used by the manufacturing site.
Include the scope and focus of QRM including a brief description of any activities, which are performed at the corporate level, and activities, which are performed locally.
Any application of the QRM system that is utilized to assess continuity of supply shall also be included.
C2.4 – Product Quality Reviews:
Brief description of methodologies used for Product Quality Reviews.
C5.1 – Preparation, revision, and distribution of necessary documentation for manufacturing:
Description of the documentation system utilized at the manufacturing site (i.e. electronic, manual).
When documents and records are stored or archived off-site (including pharmacovigilance data, when applicable):
List types of documents/records; Name and address of storage site, and an estimate of document retrieval time required from the off-site archive.
This shall include but not limited to:
Documents such as Batch Manufacturing and Packing Records (BMR & BPR),
Analytical Test Procedures,
Scale Up reports,
Validation protocol Reports,
Technology Transfer documents,
Training material and records,
Analytical Worksheets registers formats etc.
Responsibility for the preparation revision and distribution of documents.
Storage and handling of Master Documents.
Brief Description for Documentation on:
Raw material specifications
Packaging component specifications
Standard process instructions including packaging
Batch records including packaging
Product quality review/Annual product review
QA release procedures
Retention Period for Documents
Arrangements for any Electronic records / Backups
If documents and records are stored or archived off-site, List of types of documents/records; Name and address of storage site, and an estimate of the time required retrieving documents from the off-site archive.
C5.2 – Other Documentation Related to Product Quality – Site Master File (SMF):
This shall include but not limited to:
Specifications for disposables i.e. cleaning materials
Standard operating procedure
Quality Control Procedures
Computer program specifications
Documentation control of process deviations
Calibration and test documents
Reconciliation of bathes of raw materials, bulk product, major packing Components i.e. product-contact and printed material.
C5.3 – Additional Documentation :
List and briefly explain the use of any additional standard documentation used routinely.
C6 – Production – Site Master File (SMF):
Type of Products: In this section of the site master file (SMF), provide a reference to Appendix 1 or 2.
The type of products manufactured includes the following:
List of all dosage forms of both human and veterinary products, which are manufactured on site.
List of all dosage forms for investigational medicinal products (IMP) manufactured for any clinical trials on-site, and when different from the commercial manufacturing, information of production areas and personnel.
C6.1 – Brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters but not limited to:
Description of Manufacturing Operations.
The operations capable of being carried out at the site with the existing facilities and specify the categories of medicinal products.
If cytotoxic or hormone or radio-active substances are handled give details of the products.
Explain the production operations using flow charts.
C6.2 – Arrangements for the handling of starting materials, packaging materials, bulk, and finished products, including sampling, quarantine, release, and storage.
Identification of supplier’s lot number with the company’s lot number.
Status labeling e.g. by using labels or by computer.
Issue of materials to manufacture and package.
The control of weighing.
Identification of materials to be used for manufacturing.
Packaging shall include but not limited to:
Release of bulk, semi-finished products, packing materials.
Confirmation of identity and line clearance checks.
Records of key parameters of manufacturing.
Quarantine and release of finished products; compliance with the Marketing Authorization.
The role of the Authorized Person(s) and/or Qualified Person(s).
C6.3 – Brief description of arrangements for the handling of rejected materials and products:
Labeling of rejected materials.
Storage in Secure and separate areas.
Describe arrangements for sentencing the materials and their disposal.
Maintenance of destruction record
C6.4 – Process Validation:
Brief description of the general policy for process validation.
C6.5 – Reprocessing or Reworking:
Describe the policy for reprocessing or reworking.
C7 – Quality Control – Site Master File (SMF):
C7.1 – Brief description of the Quality Control activities carried out at the manufacturing site in terms of physical, chemical, and microbiological and biological testing, and the procedures for the release of finished products.
Activities of the Quality Control Department shall include but not limited to:
Briefly describe the activities of analytical testing, packaging, component testing, and microbiological testing.
If the review of batch documentation and release of final documentation takes place in QC.
Outline the involvement in the arrangements for the preparation, revision, and distribution of documents in particular those for specific test methods and release criteria if not mentioned elsewhere.
Packaging Material and Raw material Testing.
In-process and Finished Product Testing.
C8 – Distribution, Product Defect, Complaint, and Product Recall:
C8.1 – Description of Storage and Distribution Practices – Site Master File (SMF):
Storage and Distribution shall include but not limited to:
Description of Storage and Distribution Practices
Details of warehouse security
How are the materials stored e.g. pallet racking?
How is the status of products controlled e.g. by computer, by the label?
Isolation of reject material securely
Methods of distribution
Dispatch order system to ensure first expire/first out and identification of the lot number
Records of Distribution
Types (wholesale license holders, manufacturing license holders, etc) and locations (EU/EEA, USA, etc) of the companies to which the products are shipped from the site.
Brief description of the system to ensure appropriate environmental conditions during transit, e.g. temperature monitoring/control.
Brief that retained records permit full batch traceability from the factory to the customer, in terms of the date of sale, customer details, and quantity dispatched.
Arrangements for product distribution and methods by which product traceability is maintained.
Provide a description of the procedures or measures taken to prevent manufacturers’ products to fall in the illegal supply chain.
C8.2- Handling of Product Defects, Complaints, and Product Recall:
A brief description for the flow of complaints shall be explained to address the following but not limited to:
Logging of complaints
Classifying the complaints
Preparation and review of investigation reports
For how long are complaints records kept
Product Recalls: A brief description about the product recall system shall be explained which shall include but not limited to:
Responsible persons for product recalls
Details of written procedure which describes the sequence of actions to be followed including:
Retrieval of distribution data;
Notification to customers;
Receipt/segregation/inspection of returned product;
Investigation/reporting of the cause;
Reporting corrective action;
The person who notifies the Competent Authority of complaints and recall;
The Competent Authority involved in complaints and the decision to recall;
Effectiveness of recalls at below wholesale level;
List of product recalled over the last two years;
If none has been recalled, record-None.
C9 – Self Inspection – Site Master File (SMF):
C9.1 – Description of Self Inspection Program:
A short description of the self-inspection system utilized with focus on criteria used for selection of the areas to be covered during planned inspections, practical arrangements, evaluation of self-inspection, and follow-up actives.
Documented procedures and records for the self-inspection system and the follow-up actions.
C9.2 – Regulatory Inspection – Site Master File (SMF):
A brief description of inspections conducted by national authorities in the last five years.
A brief description of inspections conducted by international regulatory authorities in the last five years, including date and name/country of the competent authorities.
A copy of the current GMP certificates shall be attached.
Document and data control for Site Master File (SMF) :
Appropriate information shall be supplied in form of Annexure and the reference of the same shall be made in the point.
All the pages of the Annexure attached shall be numbered separately, i.e. they shall not be in continuation with the page numbering system of the Site Master File (SMF).
The Site Master File (SMF) shall have a Revision history as below,
Change Control No.:
The Revision history shall be page numbered separately.
The Revision history shall serve the purpose of Site Master File (SMF) reviews starting from the first revision 00 itself.
The review of the Site Master File (SMF) shall be done within ± 30 days from the date of the Next Review.
Any revision to be done to the Site Master File (SMF) in the existing year shall be in the forms of Amendments.
The Obsolete copy of the Site Master File (SMF) shall be stamped as “OBSOLETE”, stored and destroyed as per document control SOP.
If Revision is not required after review of the Site Master File (SMF), re-certify SMF for the validity of continuing usage as per respective SOP.
QA shall issue a controlled copy of the site master file (SMF) to Factory Head for reference.
Copy of Site Master File (SMF) required by any Regulatory / Any other Agency shall be forwarded through Head – Quality/ or designee by putting the stamp of UNCONTROLLED COPY.
Uncontrolled Copy Issuance record of site master file (SMF) shall be maintained as per Annexure-4.